Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells
Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells
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DOI：
10.1016/j.cub.2005.01.052
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发表时间：
2005-03-29
期刊：
影响因子：
9.2
通讯作者：
Dubeau, L
中科院分区：
文献类型：
--
作者：
Chodankar, R;Kwang, S;Dubeau, L
携带 BRCA1 种系突变的女性到 70 岁时患卵巢癌的风险为 40% [1]，并且也容易患输卵管癌 [2-4]。鉴于排卵活动是散发性卵巢癌的一个强烈危险因素[5]，我们假设 BRCA1 表达减少可能通过影响卵巢颗粒细胞间接诱发妇科癌症。这些细胞分泌控制排卵周期并影响卵巢上皮肿瘤生长的性类固醇[6, 7]。颗粒细胞还分泌苗勒管抑制物质 (MIS)，这是一种抑制男性胚胎中女性生殖器官形成的激素 [8] 和卵巢上皮肿瘤细胞的增殖 [9, 10]。我们通过使用 Cre-lox 系统灭活小鼠卵巢颗粒细胞中的 Brca1 基因来检验这一假设。 Fsh 受体启动子的截短形式 [11] 充当 Cre 驱动程序。在这里，我们证明，颗粒细胞中 Brca1 基因的失活确实导致了卵巢和子宫角囊性肿瘤的发展。这些肿瘤携带正常的 Brca1 等位基因，支持这样的观点：Brca1 可能通过颗粒细胞分泌的效应子间接影响肿瘤的发展。
Women with germline mutations in BRCA1 have a 40% risk of developing ovarian cancer by age 70 [1] and are also predisposed to cancers of the fallopian tubes [2-4]. Given that ovulatory activity is a strong risk factor for sporadic ovarian cancer [5], we hypothesized that reduced BRCA1 expression might predispose to gynecological cancers indirectly, by influencing ovarian granulosa cells. These cells secrete sex steroids that control the ovulatory cycle and influence the growth of ovarian epithelial tumors [6, 7]. Granulosa cells also secrete mullerian inhibiting substance (MIS), a hormone that inhibits both the formation of female reproductive organs in male embryos [8] and the proliferation of ovarian epithelial tumor cells [9, 10]. We tested this hypothesis by using the Cre-lox system to inactivate the Brca1 gene in mouse ovarian granulosa cells. A truncated form of the Fsh receptor promoter [11] served as the Cre driver. Here, we show that indeed, inactivation of the Brca1 gene in granulosa cells led to the development of cystic tumors in the ovaries and uterine horns. These tumors carried normal Brca1 alleles, supporting the view that Brca1 may influence tumor development indirectly, possibly through an effector secreted by granulosa cells.