title: Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist.
abstract: Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697-4037, USA.
authors.forename: Aleksandra Jovanovic
authors.initials: AJ
authors.lastname: Poole
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yoon
authors.initials: Y
authors.lastname: Kim
authors.forename: Suh-Chin J
authors.initials: SC
authors.lastname: Lin
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Eva Y-H P
authors.initials: EY
authors.lastname: Lee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D030762:Estrous Cycle; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53; D006727:Hormone Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation; D010766:Phosphorylation; D011374:Progesterone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D025801:Ubiquitin; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D046988:Proteasome Endopeptidase Complex