""""""""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.
