Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes
Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes
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DOI：
10.1016/j.yexcr.2006.09.026
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发表时间：
2007-01-01
影响因子：
3.7
通讯作者：
Vanderhyden, Barbara C.
中科院分区：
文献类型：
--
作者：
Clark-Knowles, Katherine V.;Garson, Kenneth;Vanderhyden, Barbara C.
上皮性卵巢癌（EOC）被认为是由卵巢表面上皮（OSE）引起的;然而，这种转变背后的分子事件知之甚少。BRCA 1肿瘤抑制基因的种系突变导致发生EOC的风险显著增加，并且大部分散发性EOC显示某种BRCA 1功能障碍。使用小鼠与条件表达的Brca 1，我们灭活Brca 1在小鼠OSE和证明，这种失活的结果在发展中的癌前病变，如增生，上皮内陷，和包涵体囊肿，出现更早，比对照卵巢更多。这些变化与BRCA 1生殖系突变妇女的预防性卵巢切除标本中报告的癌前病变相似。我们还报告说，在原代培养的小鼠OSE细胞的Brca 1的失活导致增殖的抑制，由于增加的凋亡，可以拯救伴随失活的p53。这些观察结果，沿着我们发现这些细胞对DNA损伤剂顺铂显示出增加的敏感性，表明OSE细胞中Brca 1功能的丧失影响细胞生长控制和DNA损伤修复，这导致细胞行为改变，表现为体内形态学变化，这些变化比可归因于衰老的变化更早出现且数量更多。(c)2006年爱思唯尔公司All rights reserved.
Epithelial ovarian cancer (EOC) is thought to arise from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. Using mice with conditional expression of Brca1, we inactivated Brca1 in the murine OSE and demonstrate that this inactivation results in the development of preneoplastic changes, such as hyperplasia, epithelial invaginations, and inclusion cysts, which arise earlier and are more numerous than in control ovaries. These changes resemble the premalignant lesions that have been reported in human prophylactic oophorectomy specimens from women with BRCA1 germline mutation. We also report that inactivation of Brca1 in primary cultures of murine OSE cells leads to a suppression of proliferation due to increased apoptosis that can be rescued by concomitant inactivation of p53. These observations, along with our finding that these cells display an increased sensitivity to the DNA-damaging agent cisplatin, indicate that loss of function of Brca1 in OSE cells impacts both cellular growth control and DNA-damage repair which results in altered cell behavior manifested as morphological changes in vivo that arise earlier and are more numerous than what can be attributed to ageing. (c) 2006 Elsevier Inc. All rights reserved.