Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs.
Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs.
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DOI：
10.1038/labinvest.2012.58
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
Dubeau L
中科院分区：
文献类型：
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作者：
Yen HY;Gabet Y;Liu Y;Martin A;Wu NL;Pike MC;Frenkel B;Maxson R;Dubeau L
不间断的月经周期活动，不受怀孕或口服避孕药的影响，是散发性卵巢癌最重要的危险因素。月经周期的进展部分是由卵巢颗粒细胞分泌的类固醇激素如雌激素和其他激素控制的。我们之前的研究表明，携带Brca1（与人类家族性卵巢癌易感性相关的Brca1同源物）的纯合子颗粒细胞特异性敲除的小鼠，在其生殖道中发展为良性上皮肿瘤。这些肿瘤至少部分是由Brca1突变小鼠发情周期的发情前期（相当于月经周期的卵泡期）的延长引起的，导致无对抗的雌激素刺激延长。在发情前同步的突变小鼠也显示出循环雌二醇水平的增加，但这种变化在肿瘤易感性中也起作用的可能性尚未研究。我们试图确定这些激素刺激的变化是否会导致卵巢外雌激素靶向组织的可测量变化。在这里，我们发现卵巢颗粒细胞携带Brca1突变的小鼠在发情前表现出子宫内膜增殖增加，这意味着Brca1失活对雌激素刺激的影响具有短期后果，至少对这个靶器官是如此。我们进一步表明，突变小鼠的股骨小梁厚度和股骨长度增加，这是众所周知的慢性雌激素刺激的后果。在携带Brca1纯合子突变的小鼠中，颗粒细胞的雌激素生物合成增加，在模仿人类Brca1突变携带者颗粒细胞突变状态的杂合子突变中，颗粒细胞的雌激素生物合成也增加。研究结果表明，人类种系BRCA1突变虽然与癌症风险增加有关，但也可能有有益的后果，如骨骼强度增加，这可能有助于维持人类基因库中突变的BRCA1等位基因。
Incessant menstrual cycle activity, uninterrupted by either pregnancy or oral contraceptive use, is the most important risk factor for sporadic ovarian cancer. Menstrual cycle progression is partly controlled by steroid hormones such as estrogens and others that are secreted by ovarian granulosa cells. We showed earlier that mice carrying a homozygous granulosa cell specific knock out of Brca1, the homolog of BRCA1that is associated with familial ovarian cancer predisposition in humans, develop benign epithelial tumors in their reproductive tract. These tumors are driven, at least in part, by a prolongation of the proestrus phase of the estrus cycle (equivalent to the follicular phase of the menstrual cycle) in Brca1 mutant mice, resulting in prolonged unopposed estrogen stimulation. Mutant mice synchronized in proestrus also showed increased circulating estradiol levels, but the possibility that this changealso plays a role in tumor predisposition was not investigated. We sought to determine whether these changes in hormonal stimulation result in measurable changes in tissues targeted by estrogen outside the ovary. Here we show that mice carrying a Brca1 mutation in ovarian granulosa cells show increased endometrial proliferation during proestrus, implying that the effects of Brca1 inactivation on estrogen stimulation have short-term consequences, at least on this target organ. We further show that mutant mice develop increased femoral trabecular thickness and femoral length, which are well-known consequences of chronic estrogen stimulation. Estrogen biosynthesis by granulosa cells was increased not only in mice carrying a homozygous Brca1 mutation, but also in heterozygous mutants mimicking the mutational status in granulosa cells of human BRCA1 mutation carriers. The results suggestthat humangermline BRCA1 mutations, although associated with increased cancer risk, may also have beneficial consequences, such as increased bone strength, that may have contributed to the maintenance of mutated BRCA1 alleles in the human gene pool.
影响因子：
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作者：
Gruber HE;Puzanov IJ;Bennett M;Kumar V;Gordon B
通讯作者：
Gordon B