Human breast tumors are broadly divided into either luminal-like or basal-like cancers. This distinction is significant since basal-like tumors are more aggressive and afford a poor patient prognosis relative to luminal-like tumors. For reasons that are unclear, germline mutations in BRCA1 strongly predispose for poor prognosis basal-like tumors. The predisposition for basal-like tumors in BRCA1mut/+ patients could be due to (1) differences in underlying target cell populations between BRCA1mut/+ and BRCA1+/+ women or (2) differences in the genetic mutations arising within a single shared target cell type. This basic question has remained unresolved due to a lack of experimental models in which it can be addressed. We describe here a novel in vivo breast cancer system that enables the generation of tumors by introducing oncogenes into normal breast epithelium derived directly from human breast tissue. This system is unique in that it enables human-derived epithelial cells to be sorted for cell surface markers and transformed without requiring in vitro culture prior to implantation in vivo. Using this experimental system, we show that epithelial cells from BRCA1mut/+ patients give rise to tumors that exhibit multiple features of basal differentiation, in contrast to epithelial cells transformed with identical oncogenes from BRCA1+/+ patients. We show further that non-cancerous epithelial cells from BRCA1mut/+ patients already exhibit atypical differentiation even prior to the onset of cancer, in contrast to cells from BRCA1+/+ women. Remarkably, some of these differences are observable in the context of unperturbed breast tissue obtained from disease-free BRCA1mut/+ and BRCA1+/+ patients. Collectively, these findings show that the increased incidence of basal-like tumors in BRCA1mut/+ patients is a reflection of the altered differentiation of breast epithelial cells in BRCA1mut/+ patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3083.
Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX