A Murine Model for Endometrial Tumorigenesis

描述（由申请人提供）：子宫内膜癌是美国最常见的妇科恶性肿瘤，每年诊断出超过36，000例新病例。这些肿瘤中有相当一部分发生在子宫内膜增生的背景下。子宫内膜增生和癌的发展有两个主要的危险因素，一个是遗传因素，另一个是环境因素。遗传性DNA错配修复缺陷可导致约50%的子宫内膜癌发生风险。雌激素（外源性和内源性）增加妇女发生子宫内膜增生和癌症的风险。我们和其他人已经证明，体细胞（获得性）错配修复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。己烯雌酚（DES）是一种人工合成的雌激素，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的作用。将Mlh 1敲除等位基因为+/+、+/-和-/-的小鼠暴露于合成雌激素DES。将确定三种不同基因型的DES诱导生殖道异常的年龄特异性表达率和表达率。将在组织学和分子水平上描述细胞表型。表达阵列研究将用于定义正常子宫内膜、子宫内膜增生和坦率癌的遗传标记（转录组）。比较癌症和癌前病变中基因表达的总体变化将提供与表型进展相关的遗传变化的见解。此外，DES促进的缺乏错配修复的癌症与具有正常DNA错配修复的癌症的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将来的雌激素和错配修复缺失促进子宫内膜肿瘤形成的分子机制的实验提供基础。对子宫内膜肿瘤发生的分子基础的进一步了解将为预防、检测和治疗这些恶性肿瘤和其他经尿道促进和反应的癌症提供途径。

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.