Abstract
The HGF gene is transcriptionally silenced in normal differentiated breast epithelial cells, but its repression fails to occur in mammary carcinoma tissues and cell lines. The molecular mechanisms underpinning aberrant HGF expression in breast cancer cells are unknown. Here we report the discovery of a DNA element located 750 bp upstream from the transcription start site in the human HGF promoter that acts as a transcriptional repressor and is a target of deletion mutagenesis in human breast cancer cells and tissues. This HGF promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which we have termed "deoxyadenosine tract element" (DATE). Functional studies revealed that truncation mutations within DATE have profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter in human breast carcinoma cell lines. We found that 51% of African Americans and 15% of individuals of mixed European descent with breast cancer harbor a truncated DATE variant (25As or fewer) in their breast tumors and that the truncated allele is associated with cancer incidence and aberrant HGF expression. Notably, breast cancer patients with the truncated DATE variant are substantially younger than those with a wild-type genotype. We also suggest that DATE may be used as a potential genetic marker to identify individuals with a higher risk of developing breast cancer.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Adult
-
Age Factors
-
Binding Sites / genetics
-
Biomarkers
-
Black or African American / genetics
-
Breast Neoplasms / genetics*
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / pathology
-
CCAAT-Enhancer-Binding Protein-beta / genetics
-
CCAAT-Enhancer-Binding Protein-beta / metabolism
-
Carcinoma / genetics
-
Carcinoma / metabolism
-
Carcinoma / pathology
-
Cell Line, Tumor
-
Chromatin Assembly and Disassembly / genetics
-
DNA / metabolism
-
DNA-Binding Proteins / metabolism
-
Female
-
Gene Expression Regulation, Neoplastic / genetics*
-
Genotype
-
Hepatocyte Growth Factor / biosynthesis*
-
Hepatocyte Growth Factor / genetics*
-
Humans
-
Mammary Glands, Human / metabolism
-
Models, Biological
-
Poly A / genetics
-
Poly(ADP-ribose) Polymerase Inhibitors
-
Poly(ADP-ribose) Polymerases / genetics
-
Poly(ADP-ribose) Polymerases / metabolism
-
Polymorphism, Genetic / genetics*
-
Promoter Regions, Genetic / genetics*
-
Protein Binding / genetics
-
Proto-Oncogene Proteins c-met / metabolism
-
RNA, Small Interfering / genetics
-
Receptors, Growth Factor / metabolism
-
Regulatory Elements, Transcriptional / genetics*
-
Risk Factors
-
Sequence Deletion / genetics
-
Uterine Cervical Neoplasms / genetics
-
Uterine Cervical Neoplasms / metabolism
-
Uterine Cervical Neoplasms / pathology
-
White People / genetics
Substances
-
Biomarkers
-
CCAAT-Enhancer-Binding Protein-beta
-
DNA-Binding Proteins
-
HGF protein, human
-
Poly(ADP-ribose) Polymerase Inhibitors
-
RNA, Small Interfering
-
Receptors, Growth Factor
-
Poly A
-
poly(dA)
-
Hepatocyte Growth Factor
-
DNA
-
Poly(ADP-ribose) Polymerases
-
MET protein, human
-
Proto-Oncogene Proteins c-met