Cooperativity of Rb, Brca1, and p53 in Malignant Breast Cancer Evolution

Prashant Kumar, Malini Mukherjee, Jacob P.S. Johnson, Milan Patel, Bing Huey, Donna G. Albertson, Karl Simin

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1003027
JournalPLoS genetics
Volume8
Issue number11
DOIs
StatePublished - Nov 1 2012

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Kumar, P., Mukherjee, M., Johnson, J. P. S., Patel, M., Huey, B., Albertson, D. G., & Simin, K. (2012). Cooperativity of Rb, Brca1, and p53 in Malignant Breast Cancer Evolution. PLoS genetics, 8(11), [e1003027]. https://doi.org/10.1371/journal.pgen.1003027