title: A TGFβ-miR-182-BRCA1 axis controls the mammary differentiation hierarchy.
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.
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, 450 East 29th Street, New York, NY 10016, USA.
authors.forename: Haydeliz
authors.initials: H
authors.lastname: Martinez-Ruiz
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, 450 East 29th Street, New York, NY 10016, USA.
authors.forename: Irineu
authors.initials: I
authors.lastname: Illa-Bochaca
authors.affiliation: Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Coral
authors.initials: C
authors.lastname: Omene
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanniford
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco, 2840 Sutter Street, San Francisco, CA 94143, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, 450 East 29th Street, New York, NY 10016, USA. mary.barcellos-hoff@ucsf.edu.|Department of Radiation Oncology, University of California, San Francisco, 2840 Sutter Street, San Francisco, CA 94143, USA.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
mesh_terms: D000818:Animals; D019313:BRCA1 Protein; D002454:Cell Differentiation; D005260:Female; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C000605931:Brca1 protein, mouse; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins