ESTROGEN, HPV, AND CERVIX CANCER IN TRANSGENIC MICE

描述：（改编自研究者摘要）“高风险”人 乳头瘤病毒（HPV）。 如HPV 16型，与80%以上的 子宫颈癌 单独的HPV 16表达不足以诱导 致癌作用，这需要特定的辅助因子。 我们已经开发了一个 动物模型，其中一种辅助因子与HPV瘤形成、慢性 雌激素治疗，诱导多步宫颈和阴道癌变 在对照下表达HPV 16的整个早期区域的转基因小鼠中， 人角蛋白-14启动子（K14-HPV 16转基因小鼠）。 我们将 研究雌激素和雌激素之间的合作 HPV的癌基因是宫颈癌发生的主要决定因素。 的 具体目标是：1. 检查宫颈癌是否减少 减少雌激素的剂量或通过添加孕酮，以及 确定雌激素停止后致癌作用是否持续 治疗 1.1. 确定宫颈癌的雌激素阈值剂量 致癌作用 1.2. 调查宫颈肿瘤病变的生长情况，或 不依赖于外源性雌激素的癌。 1.3. 调查变更 雌激素通过孕激素诱导宫颈癌的发生。 2. 探讨雌激素受体在雌激素诱导的乳腺癌中的作用 K14-HPV 16转基因小鼠的宫颈癌发生。 2.1. 检查 雌激素受体和雌激素诱导基因的表达水平 含有雌激素反应成分的蛋白质。 2.2.1检测雌激素受体信号转导对宫颈癌的作用 通过产生和处理复合14 K-HPV 16/雌激素的致癌作用 受体敲除（ERKO）。 2.2.2. 探讨了影响 雌激素受体对雌激素诱导的宫颈癌的药理学抑制作用 致癌作用 2.3. 操纵雌激素受体的表达 生殖道的不同靶细胞，以检查 宫颈上皮和间质对宫颈癌发生的影响。 2.3.1. 确定 上皮和间质在雌激素诱导的宫颈癌中的作用 通过同时表达雌激素受体和HPV的致癌作用 ERKO小鼠鳞状上皮中的癌基因缺乏受体功能， 基质。 3. 研究HPV癌基因之间的合作机制 和雌激素的作用。 3.1. 创建转基因小鼠 使用含有HPV 16 E6、E7或E5突变的14 K-HPV 16构建体 癌基因，并研究每种HPV癌蛋白对雌激素的作用 诱发宫颈癌。 雌激素与前列腺素的协同作用 和HPV可能会导致对性激素在性行为中的作用的新见解。 宫颈癌的发生和发展。

DESCRIPTION: (adapted from the investigator's abstract) "High risk" human papillomaviruses (HPV's). such as HPV type 16, are associated with over 80% of cervical cancers. HPV16 expression alone is insufficient to induce carcinogenesis, which requires specific co-factors. We have developed an animal model in which one co-factor associated with HPV neoplasia, chronic estrogen treatment, induces multi-step cervical and vaginal carcinogenesis in transgenic mice expressing the entire early region of HPV16 under control of the human keratin-14 promoter (K14-HPV16 transgenic mice). We will investigate the hypothesis that the cooperation between estrogens and the oncogenes of HPV is a major determinant of cervical carcinogenesis. The specific aims are: 1. Examine whether cervical neoplasia is decreased by decreasing doses of estrogen or by the addition of progesterone, and determine whether carcinogenesis persist after the cessation of estrogen treatment. 1.1. Determine a threshold dose of estrogen for cervical carcinogenesis. 1.2. Investigate growth of cervical neoplastic lesions or carcinoma independent of exogenous estrogen. 1.3. Investigate alteration of estrogen induced cervical carcinogenesis by progesterone. 2. Investigate the functional role of estrogen receptor in estrogen induced cervical carcinogenesis in K14-HPV16 transgenic mice. 2.1. Examine the level of expression of the estrogen receptor, and an estrogen inducible gene containing an estrogen response element, during cervical carcinogenesis. 2.2.1 Test the contribution of estrogen receptor signaling to cervical carcinogenesis by creating and treating composite 14K-HPV16/estrogen receptor knockout (ERKO) with estrogen. 2.2.2. Investigate the effect of pharmacological inhibition of estrogen receptor on estrogen induced cervical carcinogenesis. 2.3. Manipulate expression of the estrogen receptor in different target cells of the reproductive tract to examine contributions of both epithelium and stroma to cervical carcinogenesis. 2.3.1. Determine the role of the epithelium and stroma in estrogen induced cervical carcinogenesis by expressing both the estrogen receptor and the HPV oncogenes in squamous epithelium in ERKO mice lacking receptor function in the stroma. 3. Examine the mechanisms of cooperation between HPV oncogenes and estrogen during cervical carcinogenesis. 3.1. Create transgenic mice with 14K-HPV16 constructs containing mutations in the HPV16 E6, E7, or E5 oncogenes, and investigate of each of the HPV oncoproteins to estrogen induced cervical carcinogenesis. Elucidation of synergism between estrogen and HPV may lead to new insights into the role of sex hormones in the genesis and progression of cervical cancer.