Sang-Hyuk Chung

Functional roles of female sex hormones and their nuclear receptors in cervical cancer

Abstract There has been little progress for several decades in modalities to treat cervical cancer. While the cervix is a hormone-sensitive tissue, physiologic roles of estrogen receptor α (ERα), progesterone receptor (PR), and their ligands in this tissue are poorly understood. It has hampered critical assessments of data in early epidemiologic and clinical studies for cervical cancer. Experimental evidence obtained from studies using mouse models has provided new insights into the molecular mechanism of ERα and PR in cervical cancer. In a mouse model expressing human papillomavirus (HPV) oncogenes, exogenous estrogen promotes cervical cancer through stromal ERα. In the same mouse model, genetic ablation of PR promotes cervical carcinogenesis without exogenous estrogen. Medroxyprogesterone acetate, a PR-activating drug, regresses cervical cancer in the mouse model. These results support that ERα and PR play opposite roles in cervical cancer. They further support that ERα inhibition and PR activation may be translated into valuable treatment for a subset of cervical cancers.

Estrogen Inhibits Epithelial Progesterone Receptor–Dependent Progestin Therapy Efficacy in a Mouse Model of Cervical Cancer

Although the uterine cervix responds to the female sex hormone change, the role of progesterone in cervical cancer is poorly understood. It has been shown that medroxyprogesterone acetate (MPA) regresses cervical cancer in the transgenic mouse model expressing human papillomavirus type 16 E6 and E7 oncogenes. As MPA interacts most strongly with progesterone receptor (PR), we reasoned that PR would contribute to MPA-induced regression of cervical cancer. We also hypothesized that estrogen influences the therapeutic activity of MPA because it promotes cervical cancer growth in the same mouse model. The present study showed that the deletion of Pgr in the cervical cancer cells ablated the MPA's therapeutic effect in the human papillomavirus transgenic mouse model. Additionally, estrogen attenuated cancer regression by MPA in the same model system. These observations indicate that MPA can effectively regress cervical cancer only when cancer cells express PR and estrogen levels are low. These results suggest that, if translatable, MPA should be administered when estrogen levels are low in patients with PR-positive cervical cancer.