Abstract
Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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BRCA1 Protein* / genetics
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BRCA1 Protein* / metabolism
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Breast Neoplasms* / genetics
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Breast Neoplasms* / metabolism
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Breast Neoplasms* / pathology
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Evolution, Molecular
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Mammary Glands, Animal / metabolism
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Mammary Glands, Animal / pathology
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Metabolic Networks and Pathways
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Mice
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Receptors, Progesterone / genetics
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Receptors, Progesterone / metabolism
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Retinoblastoma Protein* / genetics
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Retinoblastoma Protein* / metabolism
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Tumor Suppressor Protein p53* / genetics
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Tumor Suppressor Protein p53* / metabolism
Substances
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BRCA1 Protein
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Biomarkers, Tumor
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Estrogen Receptor alpha
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Receptors, Progesterone
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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Receptor, ErbB-2