Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist
Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist
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DOI：
10.1126/science.1130471
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发表时间：
2006-12-01
期刊：
影响因子：
56.9
通讯作者：
Lee, Eva Y. -H. P.
中科院分区：
文献类型：
--
作者：
Poole, Aleksandra Jovanovic;Li, Ying;Lee, Eva Y. -H. P.
乳腺癌易感基因BRCA 1突变的女性易患乳腺癌和卵巢癌。为什么BRCA 1蛋白特别在卵巢激素敏感组织中抑制肿瘤发展仍不清楚。我们证明，未经产的Brca 1/p53缺陷小鼠的乳腺积累侧枝，并进行广泛的肺泡形成，一种表型，只发生在野生型小鼠怀孕期间。在突变的乳腺上皮细胞中，由于蛋白酶体途径降解缺陷，孕激素受体而非雌激素受体过度表达。用孕酮拮抗剂米非司酮（RU 486）治疗Brca 1/p53缺陷小鼠可预防乳腺肿瘤发生。这些发现揭示了BRCA 1蛋白的组织特异性功能，并提高了抗孕酮治疗对BRCA 1突变个体预防乳腺癌有用的可能性。
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.