Abstract
Transferrin receptor (CD71) is involved in the cellular uptake of iron and is expressed on cells with high proliferation. It may be implicated in promoting the growth of endocrine resistant phenotypes within ER+/luminal-like breast cancer. We used a panel of in vitro cell models of acquired resistance to tamoxifen (TAMR), Faslodex (FASR) or severe oestrogen deprivation (MCF-7X) and the ER+ luminal MCF-7 parental line to determine CD71 mRNA expression and to study transferrin (Tf) effects on in vitro tumour growth and its inhibition. Furthermore, CD71 protein expression was assessed in a well-characterized series of patients with invasive breast carcinoma using tissue microarrays. Our results demonstrated a striking elevation of CD71 in all cell models of acquired resistance. Exogenous Tf significantly promoted growth in MCF-7-X and MCF-7 cells but more so in MCF-7-X; this growth was significantly reduced by Faslodex (FAS) or a phosphoinositide-3 kinase inhibitor (LY294002). Increased CD71 expression was associated with poor NPI score, tumour proliferation, basal CKs, p53, EGFR, HER2, steroid receptor negativity and shortened breast cancer specific survival (P < 0.001). On multivariate analysis, CD71 was found to be an independent prognostic factor in the ER+ cohort of patients. In conclusion, therapies of current interest in breast cancer (e.g. FAS, PI3K-inhibitors) appear able to partially impact on transferrin/CD71-promoted growth, but further investigation of this important mitogenic mechanism may assist in designing new therapeutic strategies to target highly proliferative, endocrine resistant breast cancers. CD71 appears to be a candidate marker of a subgroup of ER+/luminal-like breast cancer characterised by poor outcome and resistance to tamoxifen.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Antineoplastic Agents, Hormonal / therapeutic use*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / immunology*
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology
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Carcinoma / genetics
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Carcinoma / immunology*
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Carcinoma / mortality
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Carcinoma / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromones / pharmacology
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Drug Resistance, Neoplasm*
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Estradiol / analogs & derivatives
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Estradiol / therapeutic use
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Female
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Flavonoids / pharmacology
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Fulvestrant
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Gene Expression Regulation, Neoplastic
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Humans
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Immunohistochemistry
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Kaplan-Meier Estimate
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Middle Aged
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Morpholines / pharmacology
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Neoplasm Invasiveness
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Predictive Value of Tests
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Proportional Hazards Models
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / metabolism
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Receptors, Estrogen / drug effects
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Receptors, Estrogen / metabolism
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Receptors, Transferrin / genetics
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Receptors, Transferrin / metabolism*
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Retrospective Studies
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Reverse Transcriptase Polymerase Chain Reaction
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Risk Assessment
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Tamoxifen / therapeutic use*
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Time Factors
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Tissue Array Analysis
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Transferrin / metabolism
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Treatment Outcome
Substances
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Antigens, CD
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Antineoplastic Agents, Hormonal
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Biomarkers, Tumor
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CD71 antigen
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Chromones
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Flavonoids
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Messenger
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Receptors, Estrogen
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Receptors, Transferrin
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Transferrin
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Tamoxifen
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Fulvestrant
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Estradiol
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Mitogen-Activated Protein Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one