Conditional inactivation of Brca1, p53 and Rb in mouse ovaries results in the development of leiomyosarcomas.
Conditional inactivation of Brca1, p53 and Rb in mouse ovaries results in the development of leiomyosarcomas.
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DOI：
10.1371/journal.pone.0008534
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发表时间：
2009-12-31
期刊：
影响因子：
3.7
通讯作者：
Vanderhyden BC
中科院分区：
文献类型：
--
作者：
Clark-Knowles KV;Senterman MK;Collins O;Vanderhyden BC
上皮性卵巢癌(EOC)被认为部分起源于卵巢表面上皮(OSE)；然而，这种转化背后的分子事件却鲜为人知。BRCA1抑癌基因的胚系突变导致发生卵巢上皮性癌的风险显著增加，并且很大比例的散发性卵巢癌表现出某种类型的BRCA1功能障碍。为了建立一个可以研究BRCA1介导的转化的模型，我们以前在小鼠OSE中单独灭活了BRCA1，这导致了癌前病变的积累增加，但没有形成肿瘤。在这项研究中，我们研究了BRCA1、P53和Rb等位基因有条件表达的小鼠单独或联合表达的肿瘤形成情况。瘤内注射表达Cre重组酶的重组腺病毒灭活P53，小鼠肿瘤发生率为100%。在伴随BRCA1和P53失活的小鼠中，肿瘤进展加速，但Rb和P53没有。免疫组织化学分析将肿瘤归类为可能起源于卵巢囊的平滑肌肉瘤。在原代培养的小鼠OSE细胞中，BRCA1的失活导致了增殖的抑制，这可以通过同时失活P53和/或Rb来挽救。BRCA1缺失的OSE细胞对DNA损伤剂顺铂的敏感性增加，这种作用可以通过失活P53和/或Rb来调节。这些结果表明，BRCA1缺乏可以加速肿瘤的发展，并改变OSE细胞对化疗药物的敏感性。在某些品系的小鼠中，打算改变卵巢表面上皮基因表达的腺病毒腔内注射可能会导致邻近细胞更快地转化，从而导致平滑肌肉瘤。
Epithelial ovarian cancer (EOC) is thought to arise in part 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. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas.
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