A Murine Model for Endometrial Tumorigenesis

描述(申请人提供)：子宫内膜癌是美国最常见的妇科恶性肿瘤，每年有超过36,000例新诊断病例。这些肿瘤中有相当一部分是以子宫内膜增生症为背景的。子宫内膜增生症和子宫内膜癌的两个主要危险因素已被确定，其中一个是遗传因素，另一个是环境因素。DNA错配修复的遗传缺陷使子宫内膜癌的发生有大约50%的终生风险。雌激素(外源性和内源性)会增加妇女患子宫内膜增生症和癌症的风险。我们和其他人已经证明了错配修复中的躯体(获得性)缺陷在子宫内膜癌中很常见，进一步强调了DNA错配修复缺失在这些肿瘤中的重要性。合成雌激素己烯雌酚(DES)已被证明可诱发人类和小鼠的生殖道恶性肿瘤。然而，目前对雌激素刺激和错配修复缺失在子宫内膜肿瘤发生中的相互作用知之甚少。 我们建议通过对小鼠模型的研究来确定DNA错配修复和DES在子宫内膜肿瘤发生中所起的作用。MLH1基因敲除等位基因为+/+、+/-和-/-的小鼠将暴露在合成雌激素DES中。对于三种不同的基因类型，将确定DES引起的生殖道异常的年龄特定的外显率和表达能力。细胞表型将在组织学和分子水平上进行描述。表达阵列研究将用于确定正常子宫内膜、子宫内膜增生症和直肠癌的基因特征(转录本)。比较癌症和癌前病变中基因表达的全球变化将提供对与表型进展相关的基因变化的洞察。此外，将缺乏错配修复的DES促进的癌症与具有正常DNA错配修复的癌症进行比较，将指出错配修复缺陷癌症中被破坏的途径。这些研究的结果将为未来的实验提供基础，以了解雌激素和错配修复缺失导致子宫内膜肿瘤形成的分子机制。对子宫内膜肿瘤发生的分子基础的深入了解将为预防、检测和治疗这些恶性肿瘤和其他激素促进和反应性癌症提供途径。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in the United States, with over 36,000 new cases diagnosed each year. A substantial fraction of these tumors arise on a background of endometrial hyperplasia. Two major risk factors for the development of endometrial hyperplasia and carcinoma have been identified, one of which is genetic and the other environmental. An inherited defect in DNA mismatch repair confers a approximately 50% lifetime risk for the development of endometrial carcinoma. Estrogens (both exogenous and endogenous) increase a woman's risk for the development of endometrial hyperplasia and cancer. We and others have demonstrated that somatic (acquired) defects in mismatch repair are frequent in endometrial cancer, further emphasizing the importance of loss of DNA mismatch repair in these tumors. The synthetic estrogen, diethylstilbestrol (DES), has been shown to induce reproductive tract malignancies in humans and mice. At this time, however, little is known about how estrogenic stimulation and loss of mismatch repair interact in endometrial tumorigenesis. We propose to define the roles that DNA mismatch repair and DES play in endometrial tumorigenesis through investigation of a mouse model. Mice that are +/+, +/- and -/- for a Mlh1 knockout allele will be exposed to the synthetic estrogen, DES. The age-specific penetrance and expressivity of DES-induced reproductive tract abnormalities will be determined for the three different genotypes. The cellular phenotypes will be described histologically and at the molecular level. Expression array studies will be used to define genetic signatures (transcriptomes) for the normal endometrium, endometrial hyperplasia and frank carcinoma. Comparison of the global changes in gene expression in cancers and precancerous lesions will provide insights into the genetic changes that are associated with phenotypic progression. Furthermore, comparison of DES-promoted cancers lacking mismatch repair with those that have normal DNA mismatch repair will point to pathways that are disrupted in mismatch repair deficient cancers. The results of these studies will provide the basis for future experiments into the molecular mechanisms by which estrogens and loss of mismatch repair contribute to endometrial tumor formation. The improved understanding of the molecular basis of uterine endometrial tumorigenesis will provide avenues for the prevention, detection and treatment of these malignancies and other hormonally promoted and responsive cancers.