Suppression of Cervical Cancer by the Progesterone Receptor Signaling

Cervical cancer is the fourth-most common cancer in woman and fourth leading cause of cancer death worldwide. The majority of cervical cancer is associated with high-risk human papillomaviruses (HPVs). Their tumorigenic potential stems mainly from viral oncoproteins E6 and E7, which are best known to inactivate p53 and pRb tumor suppressor, respectively. Epidemiological evidence suggests that, in addition to persistent HPV infections, other cofactors are required for cervical cancer. Multiple pregnancies and oral contraceptive use increases the risk for cervical cancer in HPV-infected women, implicating a role of estrogen and progesterone in cervical cancer. Prior studies utilizing an HPV transgenic mouse model expressing E6 and E7 (K14E6/K14E7) have demonstrated the requirement of estrogen receptor alpha (ERα) and estradiol (E2) for cervical carcinogenesis. Accumulating evidence suggests that ERα may be important for human cervical cancer. The role of progesterone and progesterone receptor (PR) in cervical cancer remains elusive. Our laboratory has demonstrated that PR agonist medroxyprogesterone acetate (MPA) promotes regression of cervical cancer and cervical intraepithelial neoplasia (CIN) in the K14E6/K14E7 mice. Goals of my dissertation project were to determine whether cervical cancer recurs after MPA therapy and whether epithelial PR is required for therapeutic effect of MPA. Using the K14E6/K14E7 mice, I found that cervical cancer recurred even if MPA treatment was continued, and recurring cervical cancer expressed PR but was refractory to MPA. In addition to PR, MPA interacts with other nuclear receptors including glucocorticoid receptor. Using the Cre/LoxP recombination system, I found that epithelial PR promoted apoptosis and inhibited proliferation in the cervical epithelium. I also determined that epithelial PR was required for MPA-mediated regression of cervical cancer, which was inhibited by E2. My results strongly support the hypothesis that epithelial PR is ligand-dependent tumor suppressor in cervical cancer. Approximately 33% of cervical cancer expresses PR. My results suggest that PR expression may not be sufficient to benefit from MPA therapy. My results also warrants further study to determine mechanism of recurrence and therapy resistance, which will facilitate the development of a better therapy for the disease.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biology

Grantor

University of Houston

Year dc:date.issued

2016

Author dc:creator

• Mehta, Fabiola Melissa 1985-

Advisor dc:contributor.advisor

• Chung, Sang-Hyuk

Committee members dc:contributor.committeemember

• Bawa-Khalfe, Tasneem
• Frigo, Daniel E.
• Weigel, Nancy L.

• Progesterone receptor
• Cervical cancer
• Female reproductive tract

Statement dc:rights

• The 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. UH Libraries has secured permission to reproduce any and all previously published materials contained in the work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10657/3271

OAI identifier oai:identifier

oai:uh-ir.tdl.org:10657/3271