Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
PLoS One. 2009 Dec 31;4(12):e8534. doi: 10.1371/journal.pone.0008534.
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.
上皮性卵巢癌（EOC）被认为部分源于卵巢表面上皮（OSE）；然而，这种转化背后的分子事件知之甚少。BRCA1 肿瘤抑制基因的种系突变导致 EOC 的发病风险显著增加，而很大一部分散发性 EOC 显示出某种 BRCA1 功能障碍。为了生成可以研究 Brca1 介导的转化的模型，我们之前在小鼠 OSE 中单独失活 Brca1，导致癌前病变的积累增加，但没有肿瘤形成。在这项研究中，我们检查了单独或组合表达条件性 Brca1、p53 和 Rb 等位基因的小鼠中的肿瘤形成。用表达 Cre 重组酶的腺病毒在囊内注射以失活 p53，导致 100%的小鼠发生肿瘤。同时失活 Brca1 和 p53 加速了肿瘤的进展，但 Rb 和 p53 同时失活则没有。免疫组织化学分析将肿瘤分类为可能起源于卵巢囊的平滑肌肉瘤。Brca1 在小鼠 OSE 细胞的原代培养中失活导致增殖受到抑制，同时失活 p53 和/或 Rb 可以挽救这种抑制。Brca1 缺陷的 OSE 细胞对 DNA 损伤剂顺铂的敏感性增加，这种效应可以通过失活 p53 和/或 Rb 来调节。这些结果表明，Brca1 缺陷可以加速肿瘤的发展并改变 OSE 细胞对化疗药物的敏感性。旨在改变卵巢表面上皮中基因表达的腺病毒在囊内递送，可能会使某些品系的小鼠中相邻细胞更快地转化，导致平滑肌肉瘤。
