Cell-Type-Specific Requirement of Progestereone Receptor for Suppression of Cell Proliferation and Carcinogenesis in the Cervix



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Cervical cancer is the third most leading cause of cancer deaths in women worldwide. Persistent infection with high–risk human papillomaviruses (HPVs) is causally associated with cervical cancer. High–risk HPV E6 and E7 oncoproteins promote cell proliferation by inactivating p53 and pRb cellular tumor suppressors, respectively, which accelerates cervical carcinogenesis. However, HPV is not sufficient for cervical cancer. Epidemiologic evidence suggests that females sex hormones contribute to cervical carcinogenesis. Consistently, chronic estrogen (E2) treatment promotes cervical carcinogenesis in HPV transgenic mouse models expressing HPV16–E6 and/or HPV16–E7. Our lab has demonstrated that synthetic progestin medroxyprogesterone acetate (MPA) prevents and regresses cervical cancer in the HPV transgenic mouse model. Our lab also has demonstrated that stromal estrogen receptor alpha (ERα) mainly mediates pro–tumorigenic action of E2. The goal of my study is to determine roles of epithelial and stromal progesterone receptor (PR) in suppression of cell proliferation and cervical cancer. In Chapter 1, I investigate whether deletion of PR promotes cervical carcinogenesis without chronic E2 treatment. I found that ablation of PR expression in the cervical epithelium sensitizes HPV transgenic mice to spontaneous cervical carcinogenesis. I also found that spontaneous cervical cancers mimic ERα and PR status in cervical cancer patients, which provides a platform to study ERα–negative and PR–negative cervical cancer. In Chapter 2, I determine roles of stromal and epithelial PR in regulation of cervical epithelial cell proliferation and survival in different E2 concentrations. I found that both epithelial and stromal PR are required for P4 to exert its anti–proliferative and pro–apoptotic actions regardless of E2 concentrations. Our lab has demonstrated that epithelial PR is required for cervical cancer regression by MPA. These observations suggest that stromal PR is also required for progestin therapy to work. In other words, MPA would be effective in treating cervical cancer expressing PR in both cancer and surrounding stroma. My findings further support that PR is a tumor suppressor in cervical cancer and provide a biomarker for patient selection for a potential clinical trial.



Progesterone Receptor, Cervical Cancer, Mouse model, Epithelial PR, Stromal PR