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

Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS Genetics (Impact Factor: 7.53). 11/2012; 8(11):e1003027. DOI: 10.1371/journal.pgen.1003027
Source: PubMed


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.

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

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    • "he Rb pathways were inactivated in the mammary epithelium by the SV40 large T - antigen ( T121 ) along with condi - tional alleles of p53 and Brca1 ( Kumar et al . 2012 ; Goel et al . 2013 ) . These TgMFT121 ; Brca1f / f p53f / f ; TgWAP - Cre mice ( referred to as TBP ) develop poorly differentiated carcinomas with a triple - negative phenotype ( Kumar et al . 2012 ) . We isolated a population of cells from TBP tumors ( a6 high / b1 high ) enriched for cells with stem cell properties ( Shackleton et al . 2006 ; Stingl et al . 2006 ) , which con - stitute a relatively small fraction of tumor cells ( Fig . 2D ) . This population , which ex - presses a6B , exhibited substantially more LMa5 expression"
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