title: Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation.
abstract: Breast cancer developed in familial BRCA1 mutation carriers bears striking similarities to sporadic basal-like breast tumors. The mechanism underlying the function of BRCA1 in suppressing basal-like breast cancer remains unclear. We previously reported that the deletion of p18(Ink4c) (p18), an inhibitor of G1 cyclin Ds-dependent CDK4 and CDK6, stimulates mammary luminal progenitor cell proliferation and leads to spontaneous luminal tumor development. We report here that germline mutation of Brca1 in p18-deficient mice blocks the increase of luminal progenitor cells, impairs luminal gene expression and promotes malignant transformation of mammary tumors. Instead of the luminal mammary tumors developed in p18 single-mutant mice, mammary tumors developed in the p18;Brca1 mice, similar to breast cancer developed in familial BRCA1 carriers, exhibited extensive basal-like features and lost the remaining wild-type allele of Brca1. These results reveal distinct functions of the RB and BRCA1 pathways in suppressing luminal and basal-like mammary tumors, respectively. These results also suggest a novel mechanism--causing luminal-to-basal transformation--for the development of basal-like breast cancer in familial BRCA1 carriers and establish a unique mouse model for developing therapeutic strategies to target both luminal and basal-like breast cancers.
authors: Molecular Oncology Program, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: F
authors: F
authors: Bai
authors: M D
authors: MD
authors: Smith
authors: H L
authors: HL
authors: Chan
authors: X-H
authors: XH
authors: Pei
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018295:Neoplasms, Basal Cell / Q000235:genetics*
chemical_list: C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18