Research ArticleBREAST CANCER

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

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Sci. Signal.  06 Dec 2016:
Vol. 9, Issue 457, pp. ra118
DOI: 10.1126/scisignal.aaf5402

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TGFβ directs mammary lineage

Breast cancers are often be classified by lineage markers for specific cell types, such as the luminal subtype or the relatively more aggressive myoepithelial (also called basal-like) subtype. Mutations in the protein BRCA1 are associated with the basal-like subtype. The growth factor TGFβ suppresses tumorigenesis in various tissues, but malignant mammary epithelial cells have decreased sensitivity to TGFβ. Using mouse models, Martinez-Ruiz et al. found that loss of TGFβ promoted mammary stem cell self-renewal and skewed differentiation to myoepithelial cells through increased abundance of a microRNA (miR-182) that targets and decreases the translation of BRCA1 transcripts. Expressing BRCA1 or blocking miR-182 restored lineage commitment homeostasis in TGFβ-deficient mammary epithelial cells. The findings link two factors in breast cancer development and may have wider implications for tumorigenesis in other epithelial, ductal tissues (such as the colon, pancreas, and prostate) in which BRCA mutations are also a risk factor.

Abstract

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 contractile myoepithelial cells. It is well established that transforming growth factor–β (TGFβ) restricts mammary epithelial cell proliferation and that sensitivity to TGFβ is decreased in breast cancer. We show that TGFβ 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 Tgfb1 or transient blockade of TGFβ increased self-renewal of mammary progenitor cells in mice, cultured primary mammary epithelial cells, and also skewed lineage commitment toward the myoepithelial fate. TGFβ 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 TGFβ-deficient mammary epithelial cells restored luminal lineage commitment. These findings reveal that TGFβ 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 TGFβ dysregulation during tumorigenesis may promote distinct breast cancer subtypes.

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