The objective of our research is to understand the mechanisms of progesterone receptor (PR) in suppressing cervical cancer. Although human papillomavirus (HPV) is required for the malignancy, it is not sufficient and other non-viral factors are implicated in cervical carcinogenesis. Roles of female hormones, estrogen and progesterone have been underexplored due to lack of a relevant model system. These hormones function through their cognate receptors, estrogen receptor a (ERa) and progesterone receptor (PR). Studies using HPV transgenic mouse model have revealed that estrogen and stromal ERa are indispensable for progression of cervical neoplastic disease. Our hypothesis is that PR is a ligand-dependent tumor suppressor in cervical cancer. Using the HPV transgenic mouse model and our new orthotopic xenograft mouse model, three specific aims will be addressed in this study: (1) it will be determined whether epithelial PR and/or stromal PR suppresses cervical cancer; (2) genes and pathways that are regulated by PR and relevant to cervical cancer suppression will be determined by microarray analyses; and (3) the efficacy of PR agonists in treating cervical cancer will be evaluated. Epithelium-specific or stroma-specific Cre mice will be used to delete PR in a cell type-specific manner. Also employed will be orthotopic xenograft mouse model in which human cervical cancer cells (PR+ or PR-) will be injected to cervix of immunocompromised mice. HPV vaccines hold promise in reducing cervical cancer incidence; however, they are not effective for all high-risk HPV types and women who are already infected. Current therapies are not effective for high-grade cervical diseases, leading to ~250,000 death every year worldwide. These studies will provide further understanding of pathogenesis of cervical cancer and thereby facilitate the development of a new effective therapy for the disease.

Public Health Relevance

Cervical cancer remains the third most frequent cancer and fourth leading cause of death by cancer in women worldwide. Although HPV vaccines are effective in preventing cervical cancer, they are not predicted to reduce the cancer incidence until 2040. Meanwhile, more than a quarter of a million women will continue to die from this cancer every year. Our research is to better understand pathogenesis of the disease, which will facilitate the development of an efficient therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA188646-02
Application #
9033107
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Houston
Department
Type
Organized Research Units
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Mehta, Fabiola F; Baik, Seunghan; Chung, Sang-Hyuk (2017) Recurrence of cervical cancer and its resistance to progestin therapy in a mouse model. Oncotarget 8:2372-2380
Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C et al. (2016) Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus. Oncotarget 7:17455-67
Chung, Sang-Hyuk (2015) Targeting female hormone receptors as cervical cancer therapy. Trends Endocrinol Metab 26:399-401