Abstract
Abstract Tumor histopathology is a strong predictor of patient mortality, although the molecular and cellular factors that are responsible for this phenotypic diversity remain poorly understood. Women with inherited mutations in the BRCA1 gene have increased risk for the development of breast cancer, but also exhibit a specific predisposition for the development of aggressive basal-like breast cancers. Here we study the interplay between inherited mutations in BRCA1 and tumor differentiation by examining the regulation of progenitor cell fate in disease-free breast tissues from BRCA1 mutation carriers. We demonstrate for the first time that cell populations derived from patients harboring mutations in BRCA1 (BRCA1mut/+) give rise to tumors with increased basal differentiation, relative to cells obtained from BRCA1+/+ patients. Molecular analysis of disease-free breast tissues from BRCA1mut/+ patients revealed significant defects in epithelial progenitor cells that are present prior to cancer incidence. Moreover, we discovered that the transcriptional repressor Slug is an important functional regulator of human breast progenitor cell lineage commitment and differentiation and that it is aberrantly expressed in BRCA1mut/+ tissues and cells prior to neoplastic transformation. In addition, Slug expression is necessary for the increased basal-like phenotypes prior to and following neoplastic transformation. These findings demonstrate that the genetic background of patient populations, in addition to affecting incidence rates, significantly impacts progenitor cell fate commitment and therefore, tumor phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2011-916
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