A TGFβ-miR-182-BRCA1 axis controls the mammary differentiation hierarchy

Maintenance of mammary functional capacity during cycles of proliferation and regression depends on appropriate cell fate decisions of mammary progenitor cells to populate an epithelium consisting of secretory luminal cells and contractilemyoepithelial cells. It iswell established that transforming growth factor-beta (TGF beta) restrictsmammary epithelial cell proliferation and that sensitivity to TGF beta is decreased in breast cancer. We show that TGF beta also exerts control of mammary progenitor self-renewal and lineage commitment decisions by stringent regulation of breast cancer associated 1 (BRCA1), which controls stem cell self-renewal and lineage commitment. Either genetic depletion of TGF beta 1 or transient blockade of TGF beta increased self-renewal of mammary progenitor cells in mice, cultured primary mammary epithelial cells, and also skewed lineage commitment toward the myoepithelial fate. TGF beta stabilized the abundance of BRCA1 by reducing the abundance of microRNA-182 (miR-182). Ectopic expression of BRCA1 or antagonism of miR-182 in cultured TGF beta-deficient mammary epithelial cells restored luminal lineage commitment. These findings reveal that TGF beta modulation of BRCA1 directs mammary epithelial cell fate and, because stem or progenitor cells are thought to be the cell of origin for aggressive breast cancer subtypes, suggest that TGF beta dysregulation during tumorigenesis may promote distinct breast cancer subtypes.