Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist.
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.
Poole
Aleksandra Jovanovic
AJ
Department of Biological Chemistry, University of California, Irvine, CA 92697-4037, USA.
Li
Ying
Y
Kim
Yoon
Y
Lin
Suh-Chin J
SC
Lee
Wen-Hwa
WH
Lee
Eva Y-H P
EY
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
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