Genetic Predisposition Directs Breast Cancer Phenotype by Dictating Progenitor Cell Fate

SummaryWomen with inherited mutations in the BRCA1 gene have increased risk of developing breast cancer but also exhibit a predisposition for the development of aggressive basal-like breast tumors. We report here that breast epithelial cells derived from patients harboring deleterious mutations in BRCA1 (BRCA1mut/+) give rise to tumors with increased basal differentiation relative to cells from BRCA1+/+ patients. Molecular analysis of disease-free breast tissues from BRCA1mut/+ patients revealed defects in progenitor cell lineage commitment even before cancer incidence. Moreover, we discovered that the transcriptional repressor Slug is an important functional suppressor of human breast progenitor cell lineage commitment and differentiation and that it is aberrantly expressed in BRCA1mut/+ tissues. Slug expression is necessary for increased basal-like phenotypes prior to and after 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.

► Lineage commitment defects in progenitor cells from BRCA1-mutation carriers
► Luminal cells from BRCA1-mutation carriers give rise to basal-like cancers
► Slug suppresses progenitor cell luminal lineage commitment
► Slug expression is necessary for regulating basal-like breast cancer phenotypes