Molecular etiology of cervicovaginal adenosis by in utero hormone exposure

本研究的最终目的是阐明宫颈和阴道癌的分子机制， 腺病的发展及其向腺癌的进展。宫颈和阴道腺病是一种 先天性异常，定义为正常鳞状细胞中存在柱状（高）腺细胞 外宫颈和阴道的（扁平）上皮。宫颈/阴道腺病已经在以下背景下进行了研究： 宫颈/阴道透明细胞腺癌（CCAC）与宫内暴露于合成 雌激素己烯雌酚（DES）。子宫内暴露于DES的女性患子宫内膜癌的风险增加。 CCAC，这被认为是由先前存在的腺病病变引起的。虽然事件发生在 在1971年DES被禁止用于孕妇后，宫颈/阴道 无DES暴露史的女性中仍有腺病和CCAC的报告，表明 还有其他因素导致了环境中的这些状况。使用小鼠模型， 我们之前已经证明，发育过程中暴露于DES会导致宫颈/阴道 通过破坏p63转录因子的表达，这是必不可少的发展， 鳞状上皮为了阐明宫颈/阴道腺病的发病机制，我们建议研究 诱导宫颈/阴道上皮发育中p63表达的信号机制，以及如何 发育期暴露于雌激素和甲状腺激素会破坏这种信号传导。当然，我们会 利用小鼠模型和报告基因系统研究p63启动子的发育调控 细胞系。此外，我们还建议研究腺病向腺癌的进展。的 宫颈和阴道CCAC通常对人乳头瘤病毒（HPV）感染呈阴性， 其病因尚不清楚。最近，PIK 3Ca或PTEN基因突变的高发生率， 导致PI 3 K（磷脂酰肌醇-3激酶）信号传导的不受控制的激活 在子宫颈的CCACs。因此，我们将探讨PI 3 K信号转导的不受控制的激活是否 使用p63和Pten双敲除小鼠模型将腺病转化为腺癌 肿瘤抑制因子从这项研究中获得的知识将帮助我们识别潜在的风险因素 存在于我们的环境中的宫颈/阴道腺病。此外，通过研究分子病因学， HPV阴性的宫颈/阴道腺癌，它可能导致早期发现和发现一个 新的和改进的治疗这种疾病。

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.