Ovulation, inclusion cysts, and p53 mutations in a mouse model of ovarian cancer

描述(由申请人提供)： 卵巢癌是西方女性中最致命的妇科恶性肿瘤。卵巢癌的病因尚不清楚，但阻止排卵的干预措施降低了患卵巢癌的风险。例如，怀孕、哺乳、使用口服避孕药和早绝经期都会降低患卵巢癌的风险。卵巢包涵体囊肿可能是卵巢癌的前驱病变。或者，卵巢癌可能发生在输卵管上皮细胞。我们已经培育了一只Smad2显性阴性(Smad2DN)小鼠，它形成了类似于输卵管上皮(输卵管内膜病)的上皮性卵巢包涵体囊肿。当这些动物被长期超数排卵六个月时，它们比正常的排卵受抑的同龄人发展出明显更多的卵巢包涵体囊，但这些囊从未发展成癌症。我们假设卵巢包涵体囊肿向癌症的转变是一个两次打击的过程。在至少其他三种卵巢癌模型中，p53突变是病变发生所必需的。因此，我们建议建立一种Smad2DN/FloxedP53双转基因小鼠，以提供第一个直接研究排卵与卵巢包涵体囊肿或输卵管上皮细胞癌变之间的联系的动物模型。具体目的1将研究卵巢表面缺失P53等位基因的Smad2DN小鼠在6个月和12个月时是否存在卵巢癌。特定目的2将通过输卵管内注射cre-重组酶来研究输卵管上皮细胞中缺失P53等位基因的Smad2DN/FloxedP53小鼠的卵巢癌。然后，特定目标3将比较超排和排卵抑制的Smad2DN/Floxedp53小鼠与OSE或试管中缺失的P53小鼠，以研究Smad和P53通路均未激活的动物排卵后癌症形成的增加。该模型的建立将为卵巢癌的进一步研究提供两条重要途径，即P53和Smad信号通路。该模型将有助于探索输卵管或卵巢中的失活是否会导致浆液性癌症。最后，将能够在这个小鼠模型中进行未来的研究，旨在产生预防卵巢癌的治疗方法。

DESCRIPTION (provided by applicant): Ovarian cancer is the most lethal gynecological malignancy among western women. The etiology of ovarian cancer is unknown, but intervention that blocks ovulation reduces the risk for developing ovarian cancer. For example, pregnancy, breast-feeding, use of oral contraceptives, and early menopause all reduce the risk for developing ovarian cancers. Ovarian inclusions cysts are possible precursor lesions of ovarian cancer. Alternatively, ovarian cancers may arise in fallopian tubal epithelial cells. We have developed a Smad2 dominant negative (Smad2DN) mouse that develops epithelial-lined ovarian inclusions cysts that resemble the fallopian epithelium (endosalpingiosis). When these animals are chronically superovulated for six months, they develop significantly more ovarian inclusions cysts than their normal littermate counterparts that are ovulation suppressed, but these cysts never developed into cancer. We hypothesize that the transition of ovarian inclusion cysts to cancer is a two hit process. In at least three other models of ovarian cancer, the mutation of p53 is required for lesions to develop. We therefore propose to develop a Smad2DN/floxedp53 bitransgenic mouse to provide the first animal model to directly investigate the link between ovulation and the transition of ovarian inclusion cysts or tubal epithelial cells into cancers. Specific Aim 1 will investigate the presence of ovarian cancer at 6 and 12 months in Smad2DN mice with the floxed p53 allele deleted in the ovarian surface using cre-recombinase intrabursal injections. Specific Aim 2 will investigate ovarian cancer in Smad2DN/floxedp53 mice with the floxed p53 allele deleted in the tubal epithelium using cre-recombinase intratubal injections. Specific Aim 3 will then compare superovulated and ovulation suppressed Smad2DN/floxedp53 mice with p53 deleted in either the OSE or the tube to investigate increased formation of cancers in response to ovulation in animals that have both the Smad and p53 pathways inactivated. Development of this model will provide two pathways for further investigation critical in ovarian cancer, p53 and Smad signaling. The model will help explore if inactivation in the tube or the ovary contributes to serous cancers. Lastly, will be able to conduct future studies in this mouse model aimed at generating therapies that prevent ovarian cancer.