title: BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development.
abstract: BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis.
authors.affiliation: Molecular Oncology Program, Department of Surgery and.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: Molecular Oncology Program, Department of Surgery and.
authors.forename: Ho Lam
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Molecular Oncology Program, Department of Surgery and.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Scott
authors.affiliation: Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.affiliation: Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jason I
authors.initials: JI
authors.lastname: Herschkowitz
authors.affiliation: Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Surgery and.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Livingstone
authors.affiliation: Molecular Oncology Program, Department of Surgery and Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: Molecular Oncology Program, Department of Surgery and Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
authors.affiliation: Molecular Oncology Program, Department of Surgery and Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. xhpei@med.miami.edu.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D054337:Cell Dedifferentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D042361:Mammary Glands, Human / Q000254:growth & development / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein