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组织中柱状(高)腺细胞的存在 宫颈和阴道(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)与宫内暴露于合成的 雌激素己烯雌酚(DES)。在子宫内暴露于DES的妇女患上DES的风险增加 CCAC，被认为是由先前存在的腺病病变引起的。尽管偶发事件 1971年禁止孕妇使用DES后显著下降，宫颈/阴道 在没有DES暴露史的女性中仍有腺病和CCAC的报道，这表明 还有其他因素导致了环境中的这些状况。使用老鼠模型， 我们以前已经证明，发育过程中暴露于DES会导致宫颈/阴道 通过干扰p63转录因子的表达而导致的腺病，而p63转录因子在腺病的发生发展中是必不可少的 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 在发育中的宫颈/阴道上皮中诱导p63表达的信号机制以及如何 发育过程中暴露于雌激素和甲状腺激素会破坏这一信号。首先，我们将 用小鼠模型和报告基因检测系统研究p63启动子的发育调控 用细胞系。此外，我们还建议对腺病向腺癌的进展进行研究。这个 宫颈和阴道宫颈鳞癌通常对人类乳头状瘤病毒(HPV)感染呈阴性反应，以及 他们的病因还不清楚。近年来，PIK3CA或PTEN基因突变高发 导致PI3K(磷脂酰肌醇-3激酶)信号失控激活的报道 在宫颈鳞癌中。因此，我们将探讨PI3K信号的非受控激活 利用p63和pten双基因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 存在于我们的宫颈/阴道腺病的环境中。此外，通过研究分子病因学， 对于HPV阴性的宫颈/阴道腺癌，它可能导致早期发现和发现 这种疾病的新的和改进的治疗方法。

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.