Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 254837009, 254843006; ICD10CM: C50, C50-C50; ORPHA: 227535; DO: 1612;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.1 | {Breast cancer, invasive ductal} | 114480 | Autosomal dominant; Somatic mutation | 3 | RAD54L | 603615 |
| 2q33.1 | {Breast cancer, protection against} | 114480 | Autosomal dominant; Somatic mutation | 3 | CASP8 | 601763 |
| 2q35 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | BARD1 | 601593 |
| 3q26.32 | Breast cancer, somatic | 114480 | 3 | PIK3CA | 171834 | |
| 5q34 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | HMMR | 600936 |
| 6p25.2 | {?Breast cancer susceptibility} | 114480 | Autosomal dominant; Somatic mutation | 1 | NQO2 | 160998 |
| 6q25.1-q25.2 | Breast cancer, somatic | 114480 | 3 | ESR1 | 133430 | |
| 8q11.23 | Breast cancer, somatic | 114480 | 3 | RB1CC1 | 606837 | |
| 11p15.4 | Breast cancer, somatic | 114480 | 3 | SLC22A1L | 602631 | |
| 11q22.3 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | ATM | 607585 |
| 12p12.1 | Breast cancer, somatic | 114480 | 3 | KRAS | 190070 | |
| 13q13.1 | {Breast cancer, male, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | BRCA2 | 600185 |
| 14q32.33 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | XRCC3 | 600675 |
| 14q32.33 | Breast cancer, somatic | 114480 | 3 | AKT1 | 164730 | |
| 15q15.1 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | RAD51 | 179617 |
| 16q22.1 | Breast cancer, lobular, somatic | 114480 | 3 | CDH1 | 192090 | |
| 17p13.1 | Breast cancer, somatic | 114480 | 3 | TP53 | 191170 | |
| 17q21.33 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | PHB1 | 176705 |
| 17q23.2 | Breast cancer, somatic | 114480 | 3 | PPM1D | 605100 | |
| 17q23.2 | {Breast cancer, early-onset, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 | BRIP1 | 605882 |
A number sign (#) is used with this entry because of evidence that mutation at more than one locus can be involved in different families or even in the same case. Breast-ovarian cancer-1 (BROVCA1; 604370) can be caused by mutation in the BRCA1 gene (113705) on chromosome 17q, BROVCA2 (600185) by mutation in the BRCA2 gene (612555) on chromosome 13q12, BROVCA3 (613399) by mutation in the RAD51C gene (602774) on chromosome 17q22, and BROVCA4 (614291) by mutation in the RAD51D gene (602954) on chromosome 17q11.
Mutation in the androgen receptor gene (AR; 313700) on the X chromosome has been found in cases of male breast cancer (see 313700.0016).
Mutation in the RAD51 gene (179617) has been found in patients with familial breast cancer (179617.0001). Breast cancer susceptibility alleles have been reported in the CHEK2 gene (see 604373.0001 and 604373.0012) and in the BARD1 gene (see 601593.0001).
Furthermore, the PPM1D gene (605100) on 17q is commonly amplified in breast cancer and appears to lead to cell transformation by abrogating p53 (191170) tumor suppressor activity (Bulavin et al., 2002). Somatic mutations in the following genes have been identified in breast cancer: SLC22A18 (602631) on 11p15, TP53 (191170) on 17p13, RB1CC1 (606837) on 8q11, PIK3CA (171834) on 3q26, and AKT1 (164730) on 14q32.
An allele of the CASP8 gene (601763.0003) has been associated with reduced risk of breast cancer. An allele of the TGFB1 gene (190180.0007) has been associated with an increased risk of invasive breast cancer. An allele of the NQO1 gene (125860.0001) has been associated with breast cancer prognosis, including survival after chemotherapy and after metastasis. Variation in the HMMR gene (600936) has also been shown to modify susceptibility.
Mutations in genes responsible for various forms of Fanconi anemia (see, e.g., 227650) have been identified as susceptibility factors for breast cancer. These include BRCA2, PALB2 (610355), BRIP1 (605882), and RAD51C (602774).
Breast cancer is a feature of several cancer syndromes, including Li-Fraumeni syndrome (151623) due to germline mutations in p53; Cowden syndrome (158350) due to mutations in the PTEN gene (601728); and Peutz-Jeghers syndrome (175200) due to mutations in the STK11 gene (602216). There also appears to be an increased risk of breast and ovarian cancer in ataxia-telangiectasia (208900), and there is some evidence that heterozygotes for some mutations in the ataxia-telangiectasia mutated gene (ATM; e.g., 607585.0032) have an increased risk of breast cancer. Germline and somatic mutations in the CDH1 gene (192090) have been found in diffuse gastric and lobular breast cancer syndrome (DBLBC; 137215).
Some genomic regions have been found to be amplified in breast cancer, including 8q24, 20q13, 11q12, and 8p12-p11 (Yang et al., 2006). The NCOA3 (601937) and ZNF217 (602967) genes, located on 20q, undergo amplification in breast cancer; when overexpressed, these genes confer cellular phenotypes consistent with a role in tumor formation (Anzick et al., 1997; Collins et al., 1998).
Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement.
Cady (1970) described a family in which 3 sisters had bilateral breast cancer. Together with reports in the literature, this suggested to him the existence of families with a particular tendency to early-onset, bilateral breast cancer. The genetic basis might, of course, be multifactorial.
Anderson (1974) concluded that the sisters of women with breast cancer whose mothers also had breast cancer have a risk 47 to 51 times that in control women; a revised estimate was 39 times (Anderson, 1976). The disease in these women usually developed before menopause, was often bilateral, and seemed to be associated with ovarian function. About 30% of daughters with early-onset, bilateral breast cancer inherited the susceptibility. The risk of breast cancer to women with affected relatives is higher when the diagnosis is made at an early age and when the disease is bilateral. Ottman et al. (1983) provided tables that give the cumulative risk of breast cancer to mothers and sisters at various ages. The highest risk group is sisters of premenstrual probands with bilateral disease. Among the sisters of women with breast cancer, Anderson and Badzioch (1985) found the highest lifetime risks when the proband had bilateral disease, an affected mother (25 +/- 7.2%), or an affected sister (28 +/- 11%). The risks were reduced to 18 +/- 3.3% and 14 +/- 2.6%, respectively, with unilateral disease. An early example of familial breast cancer was provided by Broca (1866). According to the pedigree drawn by Lynch (1976), 10 women in 4 generations of the family of Broca's wife died of breast cancer. Eisinger et al. (1998) called attention to an even earlier report of hereditary breast cancer by Le Dran (1757), who related the experience of a colleague in Avignon who had diagnosed a 19-year-old nun with cancer of the right breast. The patient refused a mastectomy not only because of the pain of surgery, but also because of a belief that the operation would be futile. Her grandmother and a grandmaternal uncle died with breast cancer, and she was convinced that this malady was hereditary and that 'her blood was corrupted by a cancerous ferment natural to her family.'
Two families with an extraordinary incidence of male breast cancer and father-to-son transmission of same was reported by Everson et al. (1976). They found a suggestion of elevated urinary estrogen in 3 of the affected males. Teasdale et al. (1976) described breast cancer in 2 brothers and in a daughter of 1 brother. Kozak et al. (1986) reported breast cancer in 2 related males, an uncle and nephew. In this family and in several reported families with male breast cancer, Kozak et al. (1986) found women in the same family with breast cancer.
Soft tissue sarcomas are associated with breast cancer in Li-Fraumeni syndrome. Mulvihill (1982) used the term cancer family syndrome of Lynch (120435) for the association of colon and endometrial carcinoma and other neoplasms including breast cancer.
Seltzer et al. (1990) concluded that dermatoglyphics can help in the identification of women either with or at risk for breast cancer. They found that the presence of 6 or more whorls is associated in a statistically significant manner with breast cancer.
Marger et al. (1975) presented the cases of 2 brothers with breast cancer and reviewed the courses of 28 other previously unreported male patients. In one of the brothers, breast cancer was preceded by prostate cancer and estrogen administration, raising the possibility that the breast cancer was a metastatic deposit. The possibility of prostatic metastases was raised in 2 other patients. Demeter et al. (1990) reported breast cancer in a 64-year-old man who had had bilateral gynecomastia since childhood. His maternal grandfather had been found to have adenocarcinoma of the breast at the age of 65. His maternal grandmother had radical mastectomy for breast cancer at the age of 66 and 2 years later underwent radiation therapy for rib metastases. The proband's sister developed breast cancer at the age of 31 years and despite aggressive therapy died 1 year later with extensive metastases.
Hauser et al. (1992) reported a family in which 2 females and 2 males in 2 generations had breast cancer. Two females in the family had prophylactic bilateral mastectomy at a young age. One male developed a left breast mass and axillary node at age 59 and died of metastatic disease at age 62. His paternal uncle presented at age 57 years with bleeding from his right breast. Biopsy suggested Paget disease of the breast and he underwent mastectomy. He subsequently died at age 75 years of prostatic carcinoma. He had a daughter who developed breast cancer at age 27 years and died at age 30 with disseminated disease, and a son who developed infiltrating grade 4 adenocarcinoma of the breast at age 54.
Chang et al. (1987) showed that the noncancerous skin fibroblasts of members of a family with Li-Fraumeni syndrome (which show resistance to the killing effect of ionizing radiation) have a 3- to 8-fold elevation in expression of the MYC oncogene (190080) and an apparent activation of the RAF1 gene (164760). Normal fetal and adult skin fibroblasts show distinctive migratory behavior when plated on 3-dimensional collagen gels.
Haggie et al. (1987) found that skin fibroblasts from 13 of 15 patients with hereditary breast cancer showed fetal-like behavior compared with only 1 of 12 age-matched healthy controls. In addition, 10 of 15 first-degree relatives of patients with hereditary breast cancer showed a fetal-like fibroblast phenotype, compared with none of 7 surgical controls.
Using x-ray diffraction studies with synchrotron radiation, James et al. (1999) found that hair from breast cancer patients had a different intermolecular structure than hair from healthy subjects. All 23 patients with breast cancer, including 8 without BRCA1 mutations, had altered hair structure. Of 5 women without breast cancer but carrying BRCA1 mutations, 3 had fully different structure and 2 had partial changes in hair structure. The authors proposed hair analysis to screen for breast cancer, but suggested additional study of the sensitivity and specificity of the test.
Briki et al. (1999) repeated the studies of James et al. (1999), using scalp hair from 10 supposedly healthy people, 7 females and 3 males, and 10 breast cancer patients, all female. They irradiated a bundle of hair in a glass capillary with a 0.5-mm monochromatic x-ray beam. The diffraction patterns from healthy subjects displayed an intense ring at 4.48 +/- 0.05 nm. Eight of the 10 breast cancer patients had the same ring. These results were exactly the opposite of those observed by James et al. (1999). However, the study by Briki et al. (1999) used scalp hair rather than pubic hair.
Breast cancer metastasis occurs in a distinct pattern involving the regional lymph nodes, bone marrow, lung, and liver, but rarely other organs. By real-time quantitative PCR, immunohistochemistry, and flow cytometric analysis, Muller et al. (2001) found that CXCR4 is highly expressed in primary and metastatic human breast cancer cells but is undetectable in normal mammary tissue, whereas CCR7 (600242) is highly expressed in normal tissue and is upregulated in breast cancer cells. Quantitative PCR analysis also detected peak expression levels of the CXCR4 ligand, CXCL12 (SDF1; 600835) in lymph nodes, lung, liver, and bone marrow, while the CCR7 ligand, CCL21 (602737), is most abundant in lymph nodes, the organs to which primary breast cancer cells preferentially migrate. Analysis of malignant melanomas determined that in addition to CXCR4 and CCR7, these tumors also had high levels of CCR10 (600240); its primary ligand is CCL27 (604833), a skin-specific chemokine involved in the homing of memory T cells into the skin. Flow cytometric analysis and confocal laser microscopy demonstrated that either CXCL12 or CCL21 induces high levels of F-actin polymerization and pseudopod formation in breast cancer cells. These chemokines, as well as lung and liver extracts, also induce directional migration of breast cancer cells in vitro, which can be blocked by antibodies to CXCR4 or CCL21. Histologic and quantitative PCR analyses showed that metastasis of intravenously or orthotopically injected breast cancer cells could be significantly decreased in SCID mice by treatment with anti-CXCR4 antibodies. Muller et al. (2001) proposed that the nonrandom expression of chemokine receptors in breast cancer and malignant melanoma, and probably in other tumor types, indicates that small molecule antagonists of chemokine receptors (e.g., Hendrix et al. (2000)) may be useful to interfere with tumor progression and metastasis in tumor patients.
Liotta (2001) reviewed the theories explaining the bias of metastases toward certain organs and addressed questions raised by the work of Muller et al. (2001).
Certain breast tumors are characterized by a high prediction uncertainty ('low-confidence') based on ESR1 (133430) expression status. Kun et al. (2003) analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ESR-subtype discrimination. Patients with 'low-confidence' ESR-positive tumors exhibited a significantly worse overall survival (p = 0.03) and shorter time to distant metastasis (p = 0.004) compared with their 'high-confidence' ESR-positive counterparts, indicating that the 'high' and 'low-confidence' binary distinction is clinically meaningful. Elevated expression of ERBB2 (164870) was significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ESR1, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2-positive samples are not known to be estrogen responsive. Kun et al. (2003) proposed that a significant portion of the effect of ERBB2 on ESR-positive breast tumors may involve ESR-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.
Kristiansen et al. (2002) reported an association between skewed X inactivation and breast cancer in young patients. Kristiansen et al. (2005) described the results of X inactivation analysis of 272 patients with familial breast cancer, 35 with BRCA1/BRCA2 germline mutations, and 292 with sporadic breast cancer. X inactivation pattern was determined by PCR analysis of the highly polymorphic CAG repeat in the androgen receptor gene (AR; 213700). Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation, defined as 90% or more of cells preferentially expressing one X chromosome. There was also a strong tendency for middle-aged patients with sporadic breast cancer to be more skewed than middle-aged controls. No association was found, however, between skewed X inactivation and breast cancer for BRCA1/BRCA2 patients. Kristiansen et al. (2005) interpreted the results as indicating that skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X-linked genes.
The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. Podsypanina et al. (2008) reported that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes Myc (190080) and Kras bearing the gly12 to asp mutation (190070.0005), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogenic induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors.
Hurtado et al. (2008) showed that estrogen-estrogen receptor (ESR; see 133430) and tamoxifen-ESR complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. Hurtado et al. (2008) implicated the paired box-2 gene product (PAX2; 167409) in a previously unrecognized role, as a crucial mediator of ERS repression of ERBB2 by the anticancer drug tamoxifen. Hurtado et al. (2008) showed that PAX2 and the ER coactivator AIB1/SRC3 (601937) compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ESR-PAX2 links these 2 breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ESR-positive luminal tumors by circumventing this repressive mechanism. Hurtado et al. (2008) concluded that their data provided mechanistic insight into the molecular basis of endocrine resistance in breast cancer.
Using microarray analysis, Miller et al. (2008) found increased expression of MIRN221 (300568) and MIRN222 (300569) in human breast cancer cells that were resistant to tamoxifen compared to parental cancer cells that were sensitive to tamoxifen. MIRNR221 and MIRNR222 expression was also increased about 2-fold in ERBB2-positive breast cancer cells that are known to be resistant to tamoxifen. Increased expression of the microRNAs was associated with decreased expression of the cell cycle inhibitor CDKN1B (600778). Ectopic expression of MIRN221 or MIRN222 rendered sensitive breast cancer cells resistant, and, conversely, overexpression of CDKN1B enhanced cell death when exposed to tamoxifen.
Li et al. (2010) found a significant association between amplification of a region on chromosome 8q22 and de novo chemoresistance to anthracyclines and metastatic recurrence in human breast cancer. Within this region, overexpression of both the YWHAZ (601288) and LAPTM4B (613296) genes was found to correlate with the observations. Knockdown of either of these genes using siRNA resulting in sensitivity of tumor cells to anthracyclines. Extensive in vitro studies confirmed the effect. Further studies indicated that LAPTM4B resulted in sequestration of anthracycline and delayed entry into the nucleus, whereas YWHAZ likely protected cells from apoptosis. The findings were specific to anthracyclines.
Petrakis (1977) listed the evidence for a genetic role in breast cancer as follows: (1) family history of breast cancer, especially bilateral breast cancer; (2) marked differences in rates between certain racial groups (lower in Asians); (3) lack of major change in incidence over many years despite dramatic decline in other cancers; (4) concordance in monozygotic twins; and (5) concordance of laterality in closely related persons. Lynch et al. (1984) found evidence consistent with a hereditary breast cancer syndrome in 5% of 225 consecutively ascertained patients with verified breast cancer. From a maximum-likelihood mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and the lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. They concluded that inherited susceptibility affected only 4% of the families in the sample; multiple cases of this relatively common disease occurred in other families by chance. They pictured an extended pedigree with 14 cases of breast cancer, 3 of them in men.
The Danish twin registry (Holm et al., 1980) had 5 out of 45 MZ twins and 4 out of 77 DZ twins concordant for breast cancer; heritability was calculated at 0.3-0.4.
From complex segregation analysis of 200 Danish breast cancer pedigrees, Williams and Anderson (1984) concluded that the distribution of cases was compatible with transmission of an autosomal dominant gene. Newman et al. (1988) used complex segregation analysis to investigate patterns of breast cancer occurrence in 1,579 nuclear families. They concluded that an autosomal dominant model with a highly penetrant susceptibility allele fully explains disease clustering.
Iselius et al. (1992) reanalyzed the Danish breast cancer data collected by Jacobsen (1946), using morbid risks that incorporate mortality due to breast cancer. They interpreted the results to favor a dominant gene for familial breast cancer. No evidence of heterogeneity was found. Cases with bilateral breast cancer and males with breast cancer all belonged to families favoring a major gene. Of the cancer sites frequently reported to be associated with familial breast cancer, only ovarian cancer was significant in this study.
Houlston et al. (1992) showed that the risk of breast cancer increased progressively in inverse relationship to the age of the index patient. First-degree relatives of patients with bilateral breast cancer had a 6.43-fold increase in risk. Houlston et al. (1992) estimated that the genetic contribution to overall lifetime liability to breast cancer in relatives declined with increasing age of onset of breast cancer in the index case from 37% at 20 years to 8% by 45 years. In Iceland, Tulinius et al. (1992) likewise found that early onset and bilaterality of breast cancer increased the risk to relatives. In an analysis of a prospective cohort study, Sellers et al. (1992) found that the increase in the risk of breast cancer associated with a high waist-to-hip ratio (the circumference of the waist divided by that of the hips), low parity, or greater age at first pregnancy was more pronounced among women with a family history of breast cancer. They concluded that there are etiologic differences between familial breast cancer and the sporadic form.
Tumors are believed to emerge only when immune surveillance fails. To ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer, Chaudhuri et al. (2000) performed molecular typing of HLA alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB*03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P = 0.0001). HLA DRB1*11 alleles were also significantly overrepresented (P less than 0.0001) in controls (16.3%) as compared with patients with early-onset breast cancer (3.5%).
Ritchie et al. (2001) introduced multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, thereby improving the identification of polymorphism combinations associated with disease risk. Using simulated case-control data, they demonstrated that MDR has reasonable power to identify interactions among 2 or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control dataset, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among 4 polymorphisms from 3 different estrogen metabolism genes: COMT (116790), CYP1A1 (108330), and CYP1B1 (601771).
To study possible genetic components in breast cancer in addition to BRCA1 and BRCA2, Cui et al. (2001) conducted single-locus and 2-locus segregation analyses, with and without a polygenic background, using 3-generation families ascertained through 858 Australian women with breast cancer diagnosed at age less than 40 years. Extensive testing for deleterious mutations in BRCA1 and BRCA2 had identified 34 carriers. Their analysis suggested that, after other possible unmeasured familial factors are considered and the known BRCA1 and BRCA2 mutation carriers are excluded, there is a residual dominantly inherited risk of female breast cancer. The study also suggested that there is a substantial recessively inherited risk of early-onset breast cancer.
Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30% of the age-adjusted variation in the percentage of dense tissue. Boyd et al. (2002) undertook 2 studies of twins to determine the proportion of the residual variation in percentage of density measured by mammography that can be explained by the unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variance attributable to additive genetic factors) accounted for 60% of the variation in density in Australian twins, 67% in North American twins, and 63% in all twins studied. The authors concluded that mammographic density may be associated with an increased risk of breast cancer.
Hamilton and Mack (2003) used a novel design of a twin study by investigating twin pairs concordant or discordant for breast cancer. On the basis of the very high relative and cumulative risk to a woman who is genomically identical to a woman with cancer, disease in monozygotic twins who were both affected was considered largely to represent hereditary cancer, whereas disease in only 1 twin of a pair was believed to represent sporadic, or less heritable, disease. Cases among disease-discordant dizygotic pairs represent the same mixture of heritable and sporadic cases as those seen in ordinary case-control studies. The analysis reported by Hamilton and Mack (2003) was based on a previously described population (Peto and Mack, 2000) and included all twins in affected pairs who completed a risk factor questionnaire. To determine whether risk factors differed according to genetic susceptibility, they stratified pairs on the basis of zygosity, concordance or discordance of disease, the presence of bilateral or unilateral disease, and the presence or absence of a family history of breast cancer. Hamilton and Mack (2003) found that within disease-discordant monozygotic twins, the twin with an earlier onset of puberty did not have an increased risk of breast cancer. Within disease-concordant monozygotic pairs, the twin with earlier puberty was much more likely to receive the diagnosis first. In contrast, a later first pregnancy, lower parity, and later menopause within the pair was associated with an increased risk of breast cancer when 1 twin was affected but did not predict an earlier diagnosis when both were affected. The absence of linkage to hormonal milestones later in life suggested that most cases of hereditary breast cancer are not related to cumulative hormone exposure and that they may instead result from an unusual sensitivity to pubertal hormones. Associations between breast cancer and early menarche and those with reproductive milestones in adulthood may reflect different genotypes. Hamilton and Mack (2003) did not genotype the twins for mutations in BRCA1 or BRCA2. They suspected that few of the monozygotic concordant twins carried mutations in these genes. Contrariwise they suspected that the twins had potent combinations of common genetic variants that, individually, would be less influential. Thus, genotyping might reveal polymorphisms important in many other women.
Van't Veer et al. (2002) used DNA microarray analysis on primary breast tumors of 117 young patients and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases in patients without tumor cells in local lymph nodes at diagnosis. In addition, they established a signature that identified tumors of BRCA1 carriers. Van't Veer et al. (2002) concluded that their gene expression profile (which consists of 70 genes) could outperform all currently used clinical parameters in predicting disease outcome, and provide a strategy to select patients who would benefit from adjuvant therapy.
Pharoah et al. (2002) examined the polygenic basis of susceptibility to breast cancer. Availability of the human genome sequence makes possible the identification of individuals as susceptible to breast cancer by their genotype profile. They examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data were compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. The results suggested that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases.
Although germline mutations in the BRCA1 and BRCA2 genes account for most cases of familial breast and ovarian cancer, a large proportion of cases segregating familial breast cancer alone (i.e., without ovarian cancer) are not caused by mutations in either of these genes. Hedenfalk et al. (2003) noted that identification of additional breast cancer predisposition genes had been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/BRCA2 families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Hedenfalk et al. (2003) showed that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrated that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.
Hartmann et al. (1999) identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Their analyses suggested a reduction in the incidence of breast cancer of at least 90%.
Schroth et al. (2009) performed a retrospective analysis of German and US cohorts of women with tamoxifen-treated hormone receptor-positive breast cancer to determine whether CYP2D6 (124030) variation is associated with clinical outcome. The median follow-up of the 1,325 patients was 6.3 years. At 9 years of follow-up, the recurrence rates for breast cancer were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Schroth et al. (2009) concluded that there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes in tamoxifen-treated breast cancer.
Weigelt et al. (2011) tested the pharmacologic effects of the rapamycin analog everolimus, an allosteric MTORC1 (see FRAP1, 601231) inhibitor, and PP242, an active-site MTORC1/MTORC2 inhibitor, on a panel of 31 breast cancer cells. Cancer cells with activating PIK3CA (171834) mutations were selectively sensitive to both inhibitors, whereas those with loss-of-function PTEN (601728) mutations were resistant to treatment. In addition, a subset of cancer cells with HER2 (164870) amplification showed increased sensitivity to PP242, but not to everolimus, regardless of PIK3CA/PTEN mutation status. Both drugs exerted their effects by inducing G1 cell cycle arrest. PP42 caused reduced downstream signal transduction of the mTOR pathway as evidenced by a decrease in AKT (164730) phosphorylation. The overall results indicated that PTEN and PIK3CA have distinct functional effects on the mTOR pathway. Weigelt et al. (2011) suggested that PIK3CA mutations in breast cancer may be a predictive marker to guide the selection of patients who would benefit from mTOR inhibitor therapy.
Associations Pending Confirmation
Goldstein et al. (1989) found a suggestion of linkage to acid phosphatase (ACP1; 171500) on chromosome 2p25 (maximum lod score = 1.01 at theta = 0.001).
Narod and Amos (1990) analyzed the effects of phenocopies and genetic heterogeneity on the demonstration of linkage between a putative cancer susceptibility gene and polymorphic DNA markers.
De Jong et al. (2003) genotyped 956 breast cancer patients and 1,271 family-based controls at SNPs in TNFA (191160) and TNFB (153440), as well as at 24 microsatellite markers over the HLA region on chromosome 6p. There was a significant difference in mean haplotype sharing between patients and controls for 4 consecutive markers (D6S2671, TNFA, D6S2672, and MICA, 600169), the highest being at D6S2671 (p = 0.017). A single haplotype was more frequent and longer in moderate-risk patients than in controls. Individuals homozygous for haplotype 110-184 (D6S2672-MICA) were observed in 9.0% of moderate-risk patients and 1.5% of controls (odds ratio = 7.14), while heterozygotes were at a lower risk (odds ratio = 1.41), suggesting a recessive effect. No association was observed between the 2 SNPs in TNFA and TNFB and breast cancer risk. The authors concluded that there may be a potential role of the HLA class III subregion in susceptibility to breast cancer in patients at moderate familial risk.
Easton et al. (2007) conducted a 2-stage genomewide association study of 4,398 familial breast cancer cases, followed by a third stage in which 30 SNPs were tested for confirmation in 22,848 cases from 22 studies. The study identified 5 novel independent loci associated with breast cancer, each at a significance level of p less than 10(-7). Four plausible genes were involved with the identified SNPs: rs2981582 in FGFR2 (176943) on chromosome 10q26; rs889312 in MAP3K1 (600982) on chromosome 5; rs3817198 in LSP1 (153432) on chromosome 11p15.5; and rs12443621, rs8051542, and rs3803662 in the TNRC9 (TOX3; 611416)/LOC643714 gene on chromosome 16q. Another SNP, rs13281615, on chromosome 8q was not located in any known gene. Easton et al. (2007) found that all of these susceptibility alleles are very common in the U.K. population and thus likely show a small increased disease risk individually. However, in combination, the SNPs may become clinically significant.
In a genomewide association study of over 2,100 Icelandic patients with breast cancer, Stacey et al. (2007) identified 2 SNPs, rs13387042 and rs3803662, located on chromosomes 2q35 and 16q12, respectively, that were significantly associated with disease. The findings were replicated in 5 sample sets totaling 2,350 European and European American breast cancer patients. The overall risk was confined to estrogen receptor (see ESR1, 133430)-positive tumors. The A allele of rs13387042 had an odds ratio of 1.44 (combined p = 1.3 x 10(-13)), and the T allele of rs3803663 had an odds ratio of 1.64 (combined p = 5.9 x 10(-19))
Hunter et al. (2007) identified a SNP (rs1219648) in intron 2 of the FGFR2 gene that was significantly (p = 1.0 x 10(-10)) associated with sporadic postmenopausal breast cancer in a 2-stage genomewide association study of 1,145 and 1,776 affected individuals of European ancestry, respectively. The pooled odds ratios were 1.20 for heterozygotes and 1.64 for homozygotes.
Among 5,028 patients with breast cancer and 32,090 controls of European ancestry, Stacey et al. (2008) found that 2 SNPs on chromosome 5p12, rs4415084 and rs10941679, were associated with increased risk for estrogen receptor-positive breast cancer. The T allele of rs4415084 yielded an OR of 1.16 (P = 6.4 x 10(-10) after Bonferroni correction), and an OR of 1.14 (P = 7.5 x 10(-5)) in the replication sample. The G allele of rs10941679 yielded an OR of 1.19 (P = 2.9 x 10(-11)). The results were not significant for estrogen receptor-negative cases, suggesting that estrogen receptor-positive and estrogen receptor-negative tumors have different genetic components to their risks.
Antoniou et al. (2009) evaluated the association of SNPs rs3817198 at LSP1, rs13387042 at 2q35, and rs13281615 at 8q24 with breast cancer risk in 9,442 BRCA1 (113705) and 5,665 BRCA2 (600185) mutation carriers from 33 study centers. The minor allele (C) of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers (P trend = 2.8 x 10(-4)). The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1, P = 0.0047; BRCA2, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appeared to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations varied by mutation type depending on whether the mutated protein was predicted to be stable.
In a SNP-based genomewide scan of 41 Spanish families with non-BRCA1/BRCA2 breast cancer, with an average of 4 female breast cancer cases per family and with no blood relatives affected with ovarian or male breast cancer, Rosa-Rosa et al. (2009) found linkage to 3 regions of interest on chromosomes 3q25 (HLOD score of 3.01), 6q24 (HLOD score of 2.26), and 21q22 (HLOD score of 3.55). A subset of 13 families with bilateral breast cancer presented an HLOD of 3.13 in the 3q25 region.
By a genomewide linkage analysis of 55 high-risk Dutch breast cancer families without mutations in the BRCA1 or BRCA2 genes and replication studies in an additional 30 families, Oldenburg et al. (2008) found linkage to a region on chromosome 9q21-q22 (nonparametric multipoint lod score of 3.96 at D9S167). However, a parametric HLOD of 0.56 was also found, indicating that most families did not show linkage to this region. No pathogenic changes were found in 5 genes within the candidate region.
Zheng et al. (2009) performed a genomewide association study of 1,505 Chinese women with breast cancer and 1,522 controls, followed by replication studies in a second set of 1,554 cases and 1,576 controls and a third set of 3,472 cases and 900 controls. SNP rs2046210 at chromosome 6q25.1, located upstream of the ESR1 gene, showed strong and consistent association with breast cancer across all 3 sets. Adjusted odds ratios were 1.36 and 1.59, respectively, for genotypes A/G and A/A, compared to G/G (p value for trend was 2.0 x 10(-15)) in the pooled analysis. These results implicated chromosome 6q25.1 as a susceptibility locus for breast cancer.
Thomas et al. (2009) conducted a 3-stage genomewide association study of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility initiative. In stage 1, 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls were genotyped. In stage 2, 24,909 top SNPs in 4,547 cases and 4,434 controls were analyzed. In stage 3, 21 loci in 4,078 cases and 5,223 controls were investigated. Two new loci achieved genomewide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1 (602948), a gene in the homologous recombination DNA repair pathway. Thomas et al. (2009) also confirmed associations with loci on chromosome 2q35, 5p12, 5q11.2, 8q24, 10q26, and 16q12.1.
Ahmed et al. (2009) tested over 800 promising associations detected by Easton et al. (2007) in a further 2 stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. Ahmed et al. (2009) found strong evidence for additional susceptibility loci on 3p (rs4973768; per-allele odds ratio = 1.11, 95% confidence interval = 1.08-1.13; p = 4.1 x 10(-23)) and 17q (rs6504950; per allele odds ratio = 0.95, 95% confidence interval = 0.92-0.97, P = 1.4 x 10(-8)). Ahmed et al. (2009) postulated that the potential causative genes include SLC4A7 (603353) and NEK10 on 3p and COX11 (603648) on 17q.
Broeks et al. (2011) provided evidence that low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes, as defined by 5 tumor cell markers (ER, PR, HER2 (164870), KRT5 (148040)/KRT6A (148041), EGFR (131550)), and other pathologic and clinical features. The study included 31 case-control or cohort studies in the Breast Cancer Association Consortium (BCAC), mostly involving European women, and analyzed 10 known susceptibility loci previously identified through genomewide association studies (GWAS) (rs2981582 on 10q26, rs3803662 on 16q12, rs889312 on 5q11, rs13281615 on 8q24, rs3817198 on 11p15, rs13387042 on 2q35, rs4973768 on 3p24, and rs6504950 on 17q23), as well as 2 putative SNPs in candidate genes rs1045485/rs17468277 in CASP8 (601763) and rs1982073 in TGFB1 (190180). The association between breast cancer and these SNPs was confirmed. Six (10q26, 16q12, 8q24, 2q35, 3p24, 17q23) of the 8 loci showed stronger associations with ER+ than ER- tumors. Analysis by PR status generally showed a similar pattern, but the CASP8 and TGFB1 SNPs were more strongly related to PR- tumors. Seven loci (10q26, 16q12, 5q11, 8q24, 2q35, 3p24, and 17q23) were more significantly associated with ER+, PR+, HER2- tumors than with ER+, PR+, HER2+ tumors. Five loci were less significantly associated with triple-negative (ER-, PR-, HER2-) tumors: 16q12, 5q11, 11p15, 2q35, and TGFB1. Of these, the loci at 16q12, 2q35, and TGFB1 were also associated with KRT5/6A+ and EGFR+ tumors. Broeks et al. (2011) suggested that tumor stratification may help in the identification and characterization of novel risk factors for breast cancer subtypes.
Alanee et al. (2012) studied the frequency of the HOXB13 (604607) missense mutation G84E (rs138213197) in 1,170 patients with familial breast cancer (including 293 patients of Ashkenazi Jewish ancestry) and wildtype BRCA1 and BRCA2; 1,053 patients with sporadic breast cancer (who were not tested for BRCA1 and 2); 1,052 patients with colon cancer; and 1,650 healthy controls. Among 877 patients, 6 women with BRCA1/2-wildtype familial breast cancer who were not of Ashkenazi Jewish ancestry were carriers of the rs138213197 variant (0.7%); this rate was 7 times as high as the prevalence of the mutation among controls (0.1%) (odds ratio, 5.7; 95% confidence interval, 1.0 to 40.7; exact P = 0.02). The mutation carriers were mainly white women who were 38 to 77 years of age at diagnosis, and 4 patients who had estrogen-receptor-positive tumors. Alanee et al. (2012) observed 3 heterozygous carriers among the patients with sporadic breast cancer (0.3%), 1 heterozygous carrier among patients with colon cancer, and no carriers of the mutation among the 293 patients with breast cancer who were of Ashkenazi Jewish ancestry. Alanee et al. (2012) stated that these findings were consistent with a moderate effect size (a risk that was approximately 6 times as high as the risk among individuals without the mutation), which is greater than the risk associated with individuals with CHEK2 (604373) mutations or common variants from genomewide association studies, but less than the risk conferred by BRACA1/2 mutations. The G84E mutation had been identified in a study of prostate cancer susceptibility (see HPC9, 610997).
Orr et al. (2012) conducted a genomewide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B (RAD51L1; 602948) at 14q24.1 was significantly associated with male breast cancer risk (rs1314913, p = 3.02 x 10(-13); OR = 1.57, 95% CI 1.39-1.77). Orr et al. (2012) also refined association at 16q12.1 to rs3803662 within TOX3 (611416) (p = 3.87 x 10(-15); OR = 1.50; 95% CI 1.35-1.66).
French et al. (2013) performed an analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies and identified 3 independent association signals for estrogen receptor-positive breast cancers at chromosome 11q13. The strongest signal mapped to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 (600246) transcription and luciferase activity in reporter assays, and may be associated with low cyclin D1 (CCND1; 168461) protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Another risk association signal, rs75915166, creates a GATA3 (131320)-binding site within a silencer element. Chromatin conformation studies demonstrated that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
Meyer et al. (2013) conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. Meyer et al. (2013) identified 3 statistically independent risk signals within the 10q26 FGFR2 (176943) locus. Within risk signals 1 and 3, genetic analysis identified 5 and 2 variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and EMSA to study protein-DNA binding, Meyer et al. (2013) identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 (602294) preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit estrogen receptor-alpha (133430) to this site in an allele-specific manner, whereas E2F1 (189971) preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5-phosphorylated RNA polymerase II (see 180660), suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region Meyer et al. (2013) concluded that a role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen receptor-positive disease.
Putative 'Breast Cancer 3' (BRCA3) Locus
Breast Cancer Linkage Consortium data on 237 breast-ovarian cancer families showed that 52% were linked to BRCA1 (113705) and 32% to BRCA2 (600185). Later studies indicated that the proportion of breast cancer families attributable to these 2 genes may be smaller than initially thought. In Finnish breast cancer families with 3 or more affected cases, a mutation in the BRCA1 gene was seen in only 10% and in the BRCA2 gene in only 11% of the families (Vehmanen et al., 1997). In southern Sweden, the corresponding percentages were 23% and 11% (Hakansson et al., 1997). These studies suggested that in the Nordic populations a significant proportion of familial breast cancer is not explained by the 2 major susceptibility genes.
Kainu et al. (2000) adopted a strategy similar to that used in the identification of the locus for the Peutz-Jeghers cancer syndrome (175200), based on the Knudson 2-hit model of development: detection of somatic deletions in the wildtype gene by comparative genomic hybridization (CGH) followed by targeted linkage analysis. They performed CGH analyses of 61 tumor tissues from 37 non-BRCA1/BRCA2 breast cancer families, designated by them BRCAX. Distinction of early genetic events was facilitated by the application of 2 complementary mathematical tree models for analysis of the CGH data. In addition, they searched for deletions that were shared in tumor tissues from multiple affected cases in the same family. The studies predicted that loss of 13q was one of the earliest genetic events in hereditary cancer. In a Swedish family with 5 breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germline haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric 2-point lod score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint lod score under heterogeneity was 3.46. The BRCA2 locus was estimated to be located at a recombination fraction of 0.25 from the new locus.
Thompson et al. (2002) evaluated the contribution of the BRCA3 locus on 13q21 to breast cancer susceptibility in 128 high-risk breast cancer families of western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. (2000), was zero (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result. The proportion of linked families reported by Kainu et al. (2000) (0.65) was excluded with a high degree of confidence in the 'new' dataset. Thompson et al. (2002) concluded that if a susceptibility gene does exist at 13q21, it can account for only a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.
Exclusion Mapping
King et al. (1980) presented evidence suggestive of linkage of breast cancer to the glutamate-pyruvate transaminase gene (GPT; 138200) on chromosome 8q24. Analysis of 6 families with the disorder yielded a lod score of 1.84; all 11 families yielded a score of 1.43. However, in Mormon breast cancer pedigrees McLellan et al. (1984) excluded linkage to GPT (cumulative lod score of -3.86).
Goldstein et al. (1989) excluded linkage between breast cancer and the genes ABO, GC, GPT, MNS, and PGM1.
In 12 high-risk families with breast cancer, Hall et al. (1990) excluded linkage to the HRAS gene (190020) on 11p (lod score of -19.9).
By linkage studies, Bowcock et al. (1990) excluded the RB1 gene (614041) on 13q14 and 13q in general as the site of the primary lesion in breast cancer. Abnormality there was sought because of observation of LOH of alleles on 13q in some ductal breast tumors and because 2 breast cancer lines had been found to have an alteration in the retinoblastoma gene.
In breast cancer tissue, Pathak and Goodacre (1986) found somatic reciprocal translocations involving 1q21 and chromosomes 3, 5, 10, 11. Chen et al. (1989) demonstrated loss of heterozygosity (LOH) in the region 1q23-q32.
The most frequently occurring constitutional reciprocal translocation in man is t(11;22)(q23;q11), which has been described in more than 100 unrelated families (Iselius et al., 1983). Lindblom et al. (1994) observed a patient with this translocation and breast cancer, prompting a study of the relationship between the 2 conditions. Among 8 families with a total of 22 balanced carriers, 1 case of breast cancer was found in each of 5 families. In another family, an unknown malignancy was reported in 1 member. No other malignancies were found among these patients. The number of breast cancer cases was significantly higher than expected among the translocation carriers (P less than 0.001). In the 7 families studied, the breakpoints showed the same localization with the markers used. The information suggested the involvement of a gene on 11q and/or 22q in the pathogenesis of breast cancer.
Somatic Changes
A previously reported loss of alleles at the HRAS locus, located at 11p14, in about 20% of breast cancer tumors was confirmed by Mackay et al. (1988). Comparing tumor and blood leukocyte DNA from a consecutive series of patients with primary breast cancer, Mackay et al. (1988) found that 61% of the tumors had allele loss demonstrated with a probe located at 17p13.3.
Coles et al. (1990) mapped regions of LOH on chromosome 17 by comparing DNA of paired tumor and blood leukocyte samples. They confirmed a high frequency of LOH on 17p, where 2 distinct regions of LOH were identified in bands p13.3 and p13.1. The latter probably involves the structural gene TP53 (191170). The frequency of LOH was higher, however, at 17p13.3, and there was no correlation between allele loss at the 2 sites. Since LOH at 17p13.3 was associated with overexpression of p53 mRNA, Coles et al. (1990) suggested the existence of a gene some 20 megabases telomeric of TP53 that regulates its expression; see 113721. They concluded that lesions of this regulatory gene are involved in the majority of breast cancers. Devilee et al. (1991) reported LOH data.
Davidoff et al. (1991) found that in 11 (22%) of 49 primary invasive human breast cancers, widespread overexpression of p53 was indicated by immunohistochemical staining. The p53 gene was directly sequenced in 7 of the tumors with elevated levels of protein, and in each case a mutation that altered the coding sequence for p53 was found in a highly conserved region of the gene. Whereas 4 of these tumors contained only a mutant p53 allele, the other 3 exhibited coding sequences from both a mutant and a wildtype allele. Six tumors that were deleted at or near the p53 locus but did not express high levels of the protein were sequenced and all retained a wildtype p53 allele. This was interpreted as indicating that overexpression of the p53 protein, not allelic loss, was associated with mutation of the p53 gene.
The ARHGEF5 (600888) oncogene belongs to the DBL family of guanine nucleotide exchange factors (GEFs) for RHO GTPases. Debily et al. (2004) identified 5 novel ARHGEF5 alternative transcripts specifically expressed in breast tumors, which were predicted to generate modified or truncated proteins. Histologic features suggested that ARHGEF5 may activate RAC1 (602048), CDC42 (116952), or ARHG (179505) rather than ARHA (165390). The authors hypothesized that activation of the ARHGEF5 oncogene, possibly by variant isoforms, may play a role in proliferative breast disease.
By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.
Sjoblom et al. (2006) determined the sequence of well-annotated human protein-coding genes in 2 common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of about 90 mutant genes, but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, Sjoblom et al. (2006) identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these were not known to be genetically altered in tumors and were predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. Sjoblom et al. (2006) concluded that their data defined the genetic landscape of 2 human cancer types, provided new targets for diagnostic and therapeutic intervention, and opened fertile avenues for basic research in tumor biology.
Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007) commented on the article by Sjoblom et al. (2006), citing statistical problems that, if addressed, would result in the identification of far fewer genes with significantly elevated mutation rates. Parmigiani et al. (2007) responded that the conclusions of the above authors were inaccurate because they were based on analyses that did not fully take into account the experimental design and other critical features of the Sjoblom et al. (2006) study.
By array CGH, Yang et al. (2006) analyzed the copy number and expression level of genes in the 8p12-p11 amplicon in 22 human breast cancer specimens and 7 breast cancer cell lines. Of the 21 potential genes identified, PCR analysis and functional analysis indicated that 3 genes, LSM1 (607281), BAG4 (603884), and C8ORF4 (607702), are breast cancer oncogenes that could work in combination to influence a transformed phenotype in human mammary epithelial cells.
To catalog the genetic changes that occur during tumorigenesis, Wood et al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, Wood et al. (2007) concluded that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene 'mountains' and a much larger number of gene 'hills' that are mutated at low frequency. Wood et al. (2007) described statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. The gene mountains comprised well-known cancer genes such as APC (611731), KRAS (190070), and TP53 (191170). Furthermore, Wood et al. (2007) observed that most tumors accumulated approximately 80 mutations, and that the majority of these were harmless. Fewer than 15 mutations are likely to be responsible for driving the initiation progression or maintenance of the tumor.
Srivastava et al. (2008) found an alteration of the H2AFX (601772) gene copy number in 25 (37%) of 65 breast cancer tissues derived from patients with sporadic forms of the disorder. Gene deletion accounted for 19 (29%) of total cases and gene amplification for 6 (9%). Patients with estrogen and progesterone receptor (PGR; 607311)-positive tumors had more significantly altered copy numbers of H2AFX compared to those with ER/PR-negative tumors. None of the tissues contained H2AFX sequence alterations.
Sotiriou and Pusztai (2009) reviewed gene expression signatures in breast cancer.
Stephens et al. (2009) used a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.
Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis.
Curtis et al. (2012) presented an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumors, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single-nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in approximately 40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, Curtis et al. (2012) identified putative cancer genes, including deletions in PPP2R2A (604941), MTAP (156540), and MAP2K4 (601335). Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, estrogen-receptor-positive 11q13/14 cis-acting subgroup and a favorable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Curtis et al. (2012) concluded that their results provided a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.
To correlate the variable clinical features of estrogen-receptor-positive breast cancer with somatic alterations, Ellis et al. (2012) studied pretreatment tumor biopsies accrued from patients in 2 studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including 5 genes (RUNX1, 151385; CBFB, 121360; MYH9, 160775; MLL3, 606833; and SF3B1, 605590) previously linked to hematopoietic disorders. Mutant MAP3K1 (600982) was associated with luminal A status, low-grade histology, and low proliferation rates, whereas mutant TP53 (191170) was associated with the opposite pattern. Moreover, mutant GATA3 (131320) correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in estrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology, but most recurrent mutations are relatively infrequent. Ellis et al. (2012) suggested that prospective clinical trials based on these findings will require comprehensive genome sequencing.
Primary triple-negative breast cancers (TNBCs), a tumor type defined by lack of estrogen receptor (133430), progesterone receptor (607311), and ERBB2 (611223) gene amplification, represent approximately 16% of all breast cancers. Shah et al. (2012) showed in 104 TNBC cases that at the time of diagnosis these cancers exhibited a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing revealed that only approximately 36% of mutations are expressed. Using deep resequencing measurements of allelic abundance for 2,414 somatic mutations, Shah et al. (2012) determined in an epithelial tumor subtype the relative abundance of clonal frequencies among cases representative of the population. They showed that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than nonbasal TNBC. Although p53, PIK3CA (171834), and PTEN (601728) somatic mutations seem to be clonally dominant compared to other genes, in some tumors their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape, and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumor progression. Shah et al. (2012) concluded that their results showed that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumor clonal genotypes.
Banerji et al. (2012) reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1 (164730), GATA3, and MAP3K1, Banerji et al. (2012) discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, they identified a recurrent MAGI3-AKT3 (611223) fusion enriched in TNBC, lacking estrogen and progesterone receptors, and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.
The Cancer Genome Atlas Network (2012) analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing, and reverse-phase protein arrays. They demonstrated the existence of 4 main breast cancer classes (luminal A, luminal B, HER2 (164870)-enriched, and basal-like) when combining data from 5 platforms, each of which showed significant molecular heterogeneity. Somatic mutations in only 3 genes (TP53, PIK3CA, and GATA3) occurred at greater than 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1 with the luminal A subtype. The Cancer Genome Atlas Network (2012) identified 2 novel protein expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR (131550)/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumors with high-grade serous ovarian tumors showed many molecular commonalities, indicating a related etiology and similar therapeutic opportunities. The biologic finding of the 4 main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raised the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.
Employing a new methodology that combines cistromics, epigenomics, and genotype imputation, Cowper-Sal-lari et al. (2012) annotated the noncoding regions of the genome in breast cancer cells and systematically identified the functional nature of SNPs associated with breast cancer risk. Their results showed that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 (602294) and ESR1 (133430) and the epigenome of histone H3 lysine-4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP in the TOX3 gene (611416) within the 16q12.1 risk locus.
Rheinbay et al. (2017) performed deep sequencing in 360 primary breast cancers and developed computational methods to identify significantly mutated promoters. Clear signals were found in the promoters of 3 genes. FOXA1 (602294), a driver of hormone-receptor positive breast cancer, harbored a mutational hotspot in its promoter leading to overexpression through increased E2F (189971) binding. RMRP (157660) and NEAT1 (612769), 2 noncoding RNA genes, carried mutations that affected protein binding to their promoters and altered expression levels. Rheinbay et al. (2017) concluded that promoter regions harbor recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions.
Mutation in the BARD1 Gene on Chromosome 2q34-q35
In 7 of 126 (5.6%) index cases from Finnish families with breast and/or ovarian cancer, Karppinen et al. (2004) identified a cys557-to-ser substitution in the BARD1 gene (C557S; 601593.0001) at elevated frequency compared to healthy controls (5.6% vs 1.4%, p = 0.005). The highest prevalence of C557S was found among a subgroup of 94 patients with breast cancer whose family history did not include ovarian cancer (7.4% vs 1.4%, p = 0.001). Karppinen et al. (2004) concluded that C557S may be a commonly occurring and mainly breast cancer-predisposing allele.
Mutation in the CYP17A1 Gene on Chromosome 10q24.3
In 3 sisters with early-onset breast cancer (diagnosed at ages 34, 38, and 42 years, respectively) who did not have mutations in BRCA1 or BRCA2, Hopper et al. (2005) identified a germline R239X mutation in the CYP17A1 gene (609300.0006). A sister who was cancer-free at age 58 did not have the R239X mutation; the mutation was not found in 788 controls. Hopper et al. (2005) suggested that there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly inherited breast cancer risk.
Although Haiman et al. (2003) presented initial evidence that haplotypes in the CYP19A1 (107910) gene, which encodes the enzyme aromatase, were associated with increased risk for breast cancer, Haiman et al. (2007) did not find an association between haplotypes or SNPs in the CYP19A1 gene among 5,356 patients with invasive breast cancer and 7,129 controls composed primarily of white women of European descent. Haiman et al. (2007) found that common haplotypes spanning the coding and proximal 5-prime region of the CYP19A1 gene were significantly associated with a 10 to 20% increase in endogenous estrogen levels in postmenopausal women, but not with breast cancer.
Association with the NQO2 Gene on Chromosome 6p25
In a hospital-based study of 893 Chinese breast cancer patients and 711 Chinese cancer-free controls, Yu et al. (2009) genotyped 11 polymorphisms of the NQO2 (160998) gene, which encodes NRH:quinone oxidoreductase-2 and has enzymatic activity on estrogen-derived quinones and is able to stabilize p53 (TP53; 191170). The authors identified significant association between the incidence of breast cancer and a 29-bp insertion/deletion polymorphism (29-bp I/D; p = 0.0027; OR, 0.76) and the rs2071002 SNP (+237A-C; p = 0.0031; OR, 0.80), both of which are within the NQO2 promoter region. The findings were replicated in a second Chinese population of 403 familial/early-onset breast cancer patients and 1,039 controls. Decreased risk was associated with the D allele of 29 bp-I/D and the +237C allele of rs2071002. The susceptibility variants within NQO2 were notably associated with breast carcinomas with wildtype p53. The 29-bp insertion allele introduced a transcriptional repressor Sp3 binding sites, and the authors demonstrated that the 237A allele of rs2071002 abolished a transcriptional activator Sp1 binding site. Real-time PCR assay showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Yu et al. (2009) suggested that NQO2 is a susceptibility gene for breast carcinogenesis.
Association with Mutations in Mismatch Repair Genes
To investigate the association of mismatch repair (MMR) genes with breast cancer, Roberts et al. (2018) conducted a retrospective review of personal and family cancer history in 423 women with pathogenic or likely pathogenic germline variants in MMR genes identified via clinical multigene hereditary cancer testing: 65 in MLH1 (120436), 94 in MSH2 (609309), 140 in MSH6 (600678), and 124 in PMS2 (600259). Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in the study population with those in the general population. When evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% CI, 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer, whereas MLH1 and MSH2 were not. Roberts et al. (2018) concluded that the MMR genes MSH6 and PMS2, mutations in which cause HNPCC5 (614350) and HNPCC4 (614334), respectively, should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Tavazoie et al. (2008) searched for general regulators of cancer metastasis and found a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. They demonstrated that restoring the expression of these microRNAs in malignant cells suppressed lung and bone metastasis in human cancer cells in vivo. Of these microRNAs, miR126 (611767) restoration reduced overall tumor growth and proliferation, whereas miR335 (611768) inhibited metastatic cell invasion. miR335 regulates a set of genes whose collective expression in a large cohort of human tumors was associated with risk of distal metastasis. miR335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 (184430) and extracellular matrix component tenascin C (187380). Expression of miR126 and miR335 is lost in the majority of primary breast tumors from patients who relapse, and the loss of expression of either microRNA is associated with poor distal metastasis-free survival. Tavazoie et al. (2008) concluded that miR335 and miR126 are metastasis suppressor microRNAs in human breast cancer.
Yang et al. (2009) found that overexpression of LCN2 (600181) in clones of human MFC-7 breast cancer cells induced expression of mesenchymal markers on these cells, including vimentin (VIM; 193060) and fibronectin (FN1; 135600), and downregulated the epithelial cell marker E-cadherin (CDH1; 192090), consistent with an epithelial to mesenchymal transition. Cell motility and invasiveness were also increased. The cancer cell clones with increased LCN2 expression also showed decreased ESR1 expression and increased SLUG (SNAI2; 602150) expression. Inhibition of LCN2 in aggressive breast cancer cells (MDA-MB-231) reduced migration and suppressed the mesenchymal phenotype. Studies in mice showed that breast cancer cells with high LCN2 expression resulted in increased local invasion and lymph node metastases compared to those with low LCN2 expression. In humans, increased urinary LCN2 levels correlated with invasive breast cancer.
Overexpression of the hepatic growth factor (HGF; 142409) protein has been observed in breast cancer tissue, but not in normal breast epithelium, of some patients. Ma et al. (2009) identified a cis-acting DNA element located 750 bp upstream from the transcription start site of the human HGF promoter that acts as a transcriptional repressor. The promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which the authors termed 'deoxyadenosine tract element' (DATE). A scan of human breast cancer cells overexpressing HGF identified somatic truncating mutations within the DATE region of the HGF gene that modulated chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter. Truncating DATE variants with 25 or fewer deoxyadenosines were found in breast cancer tumors of 51% of African Americans and 15% of individuals of mixed European descent. Notably, breast cancer patients with the truncated DATE variant were substantially younger than those with a wildtype genotype.
Stephens et al. (2009) used a pair-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. They found that there were more rearrangements in some breast cancers than had been previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicated that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicated that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provided a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.
Schramek et al. (2010) demonstrated that in vivo administration of medroxyprogesterone acetate (MPA), used in women for hormone replacement therapy and contraceptives, triggers massive induction of the key osteoclast differentiation factor RANKL (602642) in mammary gland epithelial cells. Genetic inactivation of the RANKL receptor RANK (603499) in mammary gland epithelial cells prevented MPA-induced epithelial proliferation, impaired expansion of CD49f(hi) stem cell-enriched population, and sensitized these cells to DNA damage-induced cell death. Deletion of RANK from the mammary epithelium resulted in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. Schramek et al. (2010) concluded that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.
Gonzalez-Suarez et al. (2010) showed that RANK and RANKL are expressed within normal, premalignant, and neoplastic mammary epithelium, and, using complementary gain-of-function and loss-of-function approaches, defined a direct contribution of this pathway in mammary tumorigenesis. Accelerated preneoplasias and increased mammary tumor formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacologic inhibition of RANKL attenuated mammary tumor development not only in hormone- and carcinogen-treated MMTV-RANK and wildtype mice, but also in the MMTV-neu transgenic spontaneous tumor model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in preneoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 (168461) levels. Gonzalez-Suarez et al. (2010) concluded that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium.
Tan et al. (2011) examined whether RANKL (602642), RANK (603499), and IKK-alpha (600664) are involved in mammary/breast cancer metastasis. RANK signaling in mammary carcinoma cells that overexpress the protooncogene Erbb2 (also known as Neu; 164870), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(186940)+CD25(147730)+ T cells, whose major prometastatic function was RANKL production. Most RANKL-producing T cells expressed FOXP3 (300292), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (see 102540)-positive stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK-positive human breast cancer cells. Tan et al. (2011) concluded that their results were consistent with the adverse impact of tumor-infiltrating CD4+ or FOXP3+ T cells on human breast cancer prognosis and suggested that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumors to prevent recurrent metastatic disease.
Possemato et al. (2011) developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, they screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH; 606879) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of estrogen receptor-negative breast cancers. PHGDH catalyzes the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, caused a strong decrease in cell proliferation and a reduction in serine synthesis. Possemato et al. (2011) found that PHGDH suppression does not affect intracellular serine levels, but causes a drop in levels of alpha-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. Possemato et al. (2011) concluded that certain breast cancers are dependent on increased serine pathway flux caused by PHGDH overexpression.
Ross-Innes et al. (2012) mapped genomewide estrogen receptor (ER; 133430)-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases, and found that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumors from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumors revealed gene signatures that predict clinical outcome in ER-positive disease exclusively. Ross-Innes et al. (2012) found that the differential ER binding program observed in tumors from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1 (602294)-mediated reprogramming of ER binding on a rapid time scale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histologic coexpression of ER and FOXA1 in metastatic samples. By establishing transcription factor mapping in primary tumor material, Ross-Innes et al. (2012) showed that there is plasticity in ER binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.
Montagner et al. (2012) showed that SHARP1 (BHLHE41; 606200) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is upregulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1-alpha (HIF1A; 603348) and HIF2A (603349). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviors in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of the VHL tumor suppressor (608537), hypoxia, and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels.
Burns et al. (2013) showed that the DNA cytosine deaminase APOBEC3B (607110) is a probable source of somatic C-to-T mutations in breast cancer. APOBEC3B mRNA is upregulated in most primary breast tumors and breast cancer cell lines. Tumors that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53 (191170). Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Knockdown experiments showed that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression caused cell cycle deviations, cell death, DNA fragmentation, gamma-H2AX (601772) accumulation, and C-to-T mutations. Burns et al. (2013) concluded that their data suggested a model in which APOBEC3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explained how some tumors evolve rapidly and manifest heterogeneity.
Hypercholesterolemia is a risk factor for estrogen receptor (ER; 133430)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Nelson et al. (2013) showed that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and liver X receptor (see LXRA, 602423) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 (606530) and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, Nelson et al. (2013) concluded that lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.
Toy et al. (2013) conducted a comprehensive genetic analysis of 2 independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 (133430) affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding tyr537 to ser, tyr537 to asn, and asp538 to gly alterations. Molecular dynamics simulations suggested that the structures of the tyr537 to ser and asp538 to gly mutants involve hydrogen bonding of the mutant amino acids with asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drove ER-dependent transcription and proliferation in the absence of hormone and reduced the efficacy of ER antagonists.
Robinson et al. (2013) enrolled 11 patients with ER-positive metastatic breast cancer in a prospective clinical sequencing program for advanced cancers. Whole-exome and transcriptome analysis identified 6 cases that harbored mutations of ESR1 affecting its LBD, all of whom had been treated with antiestrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified 4 endometrial cancers with similar mutations of ESR1. The 5 LBD-localized ESR1 mutations identified, encoding leu536 to gln, tyr537 to ser, tyr537 to cys, tyr537 to asn, and asp538 to gly, were shown to result in constitutive activity and continued responsiveness to antiestrogen therapies in vitro.
In an analysis of whole-genome sequencing of 560 breast cancers, Nik-Zainal et al. (2016) identified 93 protein-coding cancer genes that carried probable driver mutations.
Mertins et al. (2016) described quantitative mass spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 (602907) and SKP1 (601434) to elevated expression of epidermal growth factor receptor (EGFR; 600492), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12 (615514), PAK1 (602590), PTK2 (600758), RIPK2 (603455), and TLK2 (608439). Mertins et al. (2016) demonstrated that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
Spinelli et al. (2017) found that human breast cancer cells primarily assimilate ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH; 138130); secondary reactions enable other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. Spinelli et al. (2017) concluded that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.
Using a kinomewide RNA interference-based screening method, Dasgupta et al. (2018) identified the metabolic enzyme PFKFB4 (605320) as a robust stimulator of SRC3 (601937), which coregulates the estrogen receptor (ESR1; 133430). PFKFB4 phosphorylates SRC3 at serine-857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient ser857-to-ala (S857A) mutant SRC3 abolished the SRC3-mediated transcriptional output. PFKFB4-driven SRC3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase (TKT; 606781). Dasgupta et al. (2018) identified adenosine monophosphate deaminase-1 (AMPD1; 102770) and xanthine dehydrogenase (XDH; 607633), which are involved in purine metabolism, as SRC3 targets that may or may not be directly involved in purine synthesis. Phosphorylation of SRC3 at ser857 increases its interaction with the transcription factor ATF4 (604064) by stabilizing the recruitment of SRC3 and ATF4 to target gene promoters. Ablation of SRC3 or PFKFB4 suppressed breast tumor growth in mice and prevented metastasis to the lung from an orthotopic setting, as did S857A-mutant SRC3. Dasgupta et al. (2018) found that PFKFB4 and phosphorylated SRC3 levels are increased and correlate in estrogen receptor-positive tumors, and in patients with the basal subtype, PFKFB4 and SRC3 drive a common protein signature that correlates with poor survival. Dasgupta et al. (2018) concluded that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC3 to promote aggressive metastatic tumors.
Wellenstein et al. (2019) used a panel of 16 distinct genetically engineered mouse models for breast cancer and uncovered a role for cancer-cell-intrinsic p53 (191170) as a key regulator of prometastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumor-associated macrophages to produce IL1-beta (147720), thus driving systemic inflammation. Pharmacologic and genetic blockade of WNT (see 164820) secretion in p53-null cancer cells reversed macrophage production of IL1-beta and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, Wellenstein et al. (2019) demonstrated a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands, and systemic neutrophilia that potentiates metastatic progression. Wellenstein et al. (2019) concluded that their insights illustrated the importance of the genetic makeup of breast tumors in dictating prometastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer.
Parallels may exist with breast cancer in mice, which has long been studied from the viewpoint of genetic-viral etiology and pathogenesis. This story begins with Bittner's 'milk agent,' originally discovered by Bittner (1936); using reciprocal matings between high tumor and low tumor strains, the Jackson Laboratory staff showed in 1933 that the tumor incidence in F1 females was a function of the strain of the mother. Virologists demonstrated that the mouse mammary tumor virus (MMTV, also called MuMTV) is indeed transmitted through the milk and is an RNA virus seen in its mature form as the B particle. This was the first virus universally accepted in this country as a cancer-causing virus. Some mouse strains have been shown to carry a potent MMTV transmitted in milk and also in the egg and sperm (see review by Heston and Parks, 1977). Strains of mice purged of the MMTV by foster-nursing the young on a clean strain still show a low incidence of breast cancer developing at a late age. By introducing the cancer-enhancing gene A(vy), the incidence could be raised to 90%; however, the agent was not transmitted through the milk but by both eggs and sperm.
In one strain developed by Muhlbock (1965), Bentvelzen (1972) demonstrated that the high incidence of mammary tumors was caused by an MMTV transmitted in milk, eggs, and sperm. Particles resembling B-type retroviruses have been identified in human milk (Moore et al., 1971); MMTV-related RNA has been found in some breast cancers (Axel et al., 1972) and a breast cancer cell line that releases retrovirus-like particles has been established (McGrath et al., 1974). Callahan et al. (1982) and Westley and May (1984) demonstrated sequences in normal human DNA that appear to be homologous to endogenous retroviral sequences. By transfection of NIH 3T3 mouse cells, Lane et al. (1981) demonstrated a transforming gene in a human mammary tumor cell line (MCF-7). See 164820 for information on the human homolog of the putative mammary tumor oncogene.
Familial breast cancer shares several features with hereditary tumors that satisfy the conditions predicted by the 2-hit hypothesis of Knudson (1971); tumors are frequently bilateral and multifocal. They tend to occur in premenopausal women, while the overall incidence of breast cancer shows a peak at postmenopausal age; and male relatives in high-risk families are more often affected than are males in the general population. Lundberg et al. (1987) tested their hypothesis that the pathogenesis of breast cancer in males and young females involves a chromosomal rearrangement that serves to unmask a recessive cancer gene. Lundberg et al. (1987) studied 10 cases of ductal breast cancer: 8 premenopausal females and 2 males. In 3 females and 1 male, somatic loss of constitutional heterozygosity was observed at loci on chromosome 13 in primary tumor tissue. In 2 cases, specific loss of heterozygosity at 3 distinct genetic loci along the length of chromosome 13 was observed. In a third case, concurrent loss of alleles at loci on chromosomes 2, 13, 14, and 20 was detected, whereas a fourth case showed loss of heterozygosity for chromosomes 5 and 13. In each instance, the data were consistent with loss of one of the homologous chromosomes by mitotic nondisjunction. The relative specificity of the events was suggested by the fact that analysis of loci on several other chromosomes showed retention of constitutional heterozygosity. On the other hand, analyses of other breast cancers, including comedocarcinoma, medullary carcinoma, and juvenile secretory carcinoma, showed no loss of alleles at loci on chromosome 13. Lundberg et al. (1987) interpreted these data as suggesting that in a substantial proportion of cases, the pathogenesis of ductal breast cancer involves the unmasking of a recessive locus on chromosome 13 and involvement of the same locus in heritable forms of this disease. Lundberg et al. (1987) raised the possibility of using molecular cytogenetics as an adjunct to histopathology in the diagnosis of breast tumors.
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