Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis

Date

2017-05

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Abstract

Most cervical cancers are associated with high-risk human papillomaviruses (HPVs). HPVs display tumorigenic functions in host cells mainly through viral oncogenes E6 and E7 that are best known to inhibit p53 and pRb tumor suppressor, respectively. However, HPV infection alone is not sufficient to induce cervical cancer. Other cofactors have been identified. Long-term use of oral contraceptives and multiple full-term pregnancies increase the risk of cervical cancer in women with HPV infection. Prolonged treatment of estrogen is required for initiation and maintenance of cervical cancer in HPV transgenic mice expressing E6 and E7. Genetic deletion of estrogen receptor alpha (ERα) inhibits the development of cervical cancer in the same mouse models. While these findings highlight the importance of estrogen and ERα in cervical carcinogenesis, there is little understanding of their mechanism of action. My dissertation seeks to explain how ERα contributes to cervical carcinogenesis. The main questions addressed in this dissertation are: (1) Is the DNA- binding domain (DBD) of ERα required for cervical carcinogenesis? (2) Is epithelial ERα required for cervical carcinogenesis? Genetically engineered mouse models expressing a DBD mutant or allowing a conditional deletion of ERα were used to answer these questions. The data in Chapter 1 demonstrate that point mutations within ERα DBD reduce estrogen-induced cell proliferation in the cervical epithelium. In HPV transgenic mice, ERα DBD is necessary for initiation of cervical cancer. In Chapter 2, I address the effect of specific deletion of ERα in the epithelial compartment on cervical carcinogenesis. Using epithelium-specific knockout mice, I conclude that epithelial ERα is not absolutely required for estrogen-induced cervical cancer in HPV transgenic mice. I should also note that, although almost all epithelial ERα-deficient HPV transgenic mice developed cervical neoplastic diseases, a smaller fraction of mice developed cervical cancer compared to epithelial ERα-sufficient control mice. These results are in accord with previous observations that stromal ERα signaling is required for progression of cervical neoplasia to cancer in the same mouse model. Lastly my dissertation gives a description on the establishment of a new orthotopic mouse model for human cervical cancer (Chapter 3). This novel preclinical model will be valuable in further studies to determine efficiency of drug candidates such as anti-estrogenic reagents in treating human cervical cancer.

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Keywords

Estrogen receptor alpha, Cervical cancer

Citation

Portions of this document appear in: Son, Jieun, Jung Wook Park, Paul F. Lambert, and Sang-Hyuk Chung. "Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice." Carcinogenesis 35, no. 2 (2013): 489-496.