Molecular etiology of cervicovaginal adenosis by in utero hormone exposure

描述（由申请人提供）：本研究的最终目的是阐明宫颈和阴道腺病发展及其进展为腺癌的分子机制。宫颈和阴道腺病是一种先天性异常，定义为在正常鳞状（扁平）上皮外宫颈和阴道中存在柱状（高）腺细胞。子宫颈/阴道腺病已在子宫内暴露于合成雌激素己烯雌酚（DES）相关的子宫颈/阴道透明细胞腺癌（CCAC）的背景下进行了研究。子宫内暴露于DES的女性发生CCAC的风险增加，这被认为是由先前存在的腺病病变引起的。尽管在1971年禁止DES用于孕妇后，发病率显著下降，但在没有DES暴露史的妇女中仍报告了宫颈/阴道腺病和CCAC，这表明环境中还有其他因素导致这些疾病。使用小鼠模型，我们以前已经证明，发展暴露于DES诱导宫颈/阴道腺病通过破坏p63转录因子的表达，这是必要的鳞状上皮细胞的发展。为了阐明宫颈/阴道腺病的发病机制，我们建议研究信号机制，诱导p63在发展中的宫颈/阴道上皮细胞的表达，以及如何发展暴露于雌激素和甲状腺激素破坏这种信号。首先，我们将使用小鼠模型和细胞系报告基因系统研究p63启动子的发育调控。此外，我们还建议研究腺病向腺癌的进展。宫颈和阴道CCACs通常对人乳头瘤病毒（HPV）感染呈阴性，其病因尚不清楚。近年来，有报道称宫颈癌细胞中PIK3Ca或PTEN基因的突变导致PI3K（phosphatidylinositol-3 kinase，磷脂酰肌醇-3激酶）信号的不受控制的激活。因此，我们将探索PI3K信号转导的不受控制的激活是否使用p63和Pten肿瘤抑制因子的双敲除小鼠模型将腺病转化为腺癌。从这项研究中获得的知识将帮助我们确定存在于我们的环境中的宫颈/阴道腺病的潜在危险因素。此外，通过研究HPV阴性宫颈/阴道腺癌的分子病因学，可能会导致早期发现和发现这种疾病的新的和改进的治疗方法。 公共卫生相关性：虽然子宫颈外段和阴道的腺癌被认为是由先前存在的良性腺病病变引起的，但其病因尚不清楚。该项目将通过阐明这些疾病的分子发病机制，确定外宫颈和阴道腺病和腺癌的风险因素（例如环境化学品）。

DESCRIPTION (provided by applicant): The ultimate goal of this study is to elucidate the molecular mechanisms of cervical and vaginal adenosis development and its progression to adenocarcinoma. Cervical and vaginal adenosis is a congenital anomaly defined as the presence of columnar (tall) glandular cells in normally squamous (flat) epithelium of ectocervix and vagina. Cervical/vaginal adenosis has been studied in the context of cervical/vaginal clear cell adenocaricinoma (CCAC) associated with in utero exposure to a synthetic estrogen diethylstilbestrol (DES). Women exposed to DES in utero are at increased risk of developing CCAC, which is believed to arise from preexisting adenosis lesions. Although incidences have declined significantly after DES use for pregnant women was banned in 1971, cervical/vagina adenosis and CCAC are still reported in women without history of DES exposure, suggesting that there are other factors that contribute to these conditions in the environment. Using a mouse model, we have previously demonstrated that developmental exposure to DES induces cervical/vaginal adenosis by disrupting expression of p63 transcription factor, which is essential for development of squamous epithelia. To elucidate the pathogenesis of cervical/vaginal adenosis, we propose to study signaling mechanism that induces p63 expression in developing cervical/vaginal epithelium, and how developmental exposure to estrogen and thyroid hormone disrupts this signaling. Primarily, we will study how p63 promoter is developmentally regulated using mouse model and reporter assay system with cell line. In addition, we also propose to study progression of adenosis to adenocarcinoma. The cervical and vaginal CCACs are generally negative for human papilloma virus (HPV) infection, and their etiology is not understood. Recently, high incidence of mutations in PIK3Ca or PTEN gene resulting in uncontrolled-activation of PI3K (phosphatidylinositol-3 kinase) signaling has been reported in CCACs of cervix. Therefore, we will explore whether uncontrolled-activation of PI3K signaling transforms adenosis into adenocarcinoma using double knockout mouse model for p63 and Pten tumor suppressor. The knowledge obtained from this study will help us identify potential risk factors that exist in our environment for cervical/vaginal adenosis. In addition, by studying molecular etiology of HPV-negative cervical/vaginal adenocarcinoma, it may lead to early detection and discovery of a new and improved treatment for this disease. PUBLIC HEALTH RELEVANCE: Although adenocarcinomas of ectocervix and vagina are believed to arise from preexisting benign adenosis lesions, its etiology is unknown. This project will identify the risk factor (e.g. environmental chemicals) for adenosis and adenocarcinoma of ectocervix and vagina by elucidating the molecular pathogenesis of these conditions.