ESTROGEN, HPV, AND CERVIX CANCER IN TRANSGENIC MICE

描述：(改编自调查人员的摘要)“高危”人类 乳头瘤病毒(HPV)。如HPV16型，与80%以上 子宫颈癌的风险。HPV16单独表达不足以诱导 致癌，这需要特定的辅助因素。我们已经开发出一种 一种与慢性HPV瘤变相关的辅因子动物模型 雌激素治疗，诱导多步宫颈癌和阴道癌的发生 在对照条件下表达HPV16整个早期区域的转基因小鼠 人角蛋白-14启动子(K14-HPV16转基因小鼠)。我们会 调查雌激素和雌激素之间的协同作用的假设 HPV癌基因是宫颈癌发生的主要决定因素。这个 具体目标是：1.检查宫颈肿瘤是否通过以下方式减少 减少雌激素的剂量或添加黄体酮，以及 确定停用雌激素后致癌作用是否持续 治疗。1.1.确定子宫颈雌激素的阈值剂量 致癌。1.2.调查宫颈肿瘤性病变的生长或 不依赖外源性雌激素的癌症。1.3.调查变更情况 雌激素通过孕酮诱导子宫颈癌的研究。2. 雌激素受体在雌激素诱导中的作用研究 K14-HPV16转基因小鼠的宫颈癌发生。2.1.请查看 雌激素受体和雌激素诱导基因的表达水平 在宫颈癌发生过程中，含有雌激素反应元件。 2.2.1检测雌激素受体信号对宫颈的作用 14K-HPV16/雌激素复合体的致癌作用 雌激素受体基因敲除(ERKO)。2.2.2.调查以下方面的影响 雌激素受体对雌激素诱导的宫颈病变的药理抑制作用 致癌。2.3.调控雌激素受体在卵巢癌中的表达 生殖道的不同靶细胞以检查其对 上皮和间质对宫颈癌变的影响。2.3.1。测定 上皮和间质在雌激素诱导的宫颈病变中的作用 雌激素受体和人乳头瘤病毒共同表达的致癌作用 受体功能缺失的ERKO小鼠鳞状上皮癌基因 基质。3.探讨人乳头瘤病毒癌基因间的协同作用机制 和雌激素在宫颈癌发生过程中的作用。3.1.创造转基因小鼠 具有包含HPV16E6、E7或E5突变的14K-HPV16构建体 癌基因，并研究每种HPV癌蛋白对雌激素的作用 诱导子宫颈癌的发生。雌激素之间协同作用的阐明 人乳头瘤病毒可能会导致对性激素在 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.