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

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dc.contributor.advisorChung, Sang-Hyuk
dc.contributor.committeeMemberBawa-Khalfe, Tasneem
dc.contributor.committeeMemberLin, Chin-Yo
dc.contributor.committeeMemberHan, Sang Jun
dc.creatorPark, Yuri
dc.date.accessioned2020-06-02T05:17:31Z
dc.date.createdMay 2020
dc.date.issued2020-05
dc.date.submittedMay 2020
dc.date.updated2020-06-02T05:17:32Z
dc.description.abstractCervical 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.
dc.description.departmentBiology and Biochemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/6629
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectProgesterone Receptor
dc.subjectCervical Cancer
dc.subjectMouse model
dc.subjectEpithelial PR
dc.subjectStromal PR
dc.titleCell-Type-Specific Requirement of Progestereone Receptor for Suppression of Cell Proliferation and Carcinogenesis in the Cervix
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2022-05-01
local.embargo.terms2022-05-01
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentBiology and Biochemistry, Department of
thesis.degree.disciplineBiology
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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