Persistent HPV infection and other cofactors are required for the progression of cervical cancer. Oral contraceptive use or multiple parities increases risk for cervical cancer in HPV-positive women. These risk factors have hormonal balance skewed toward estrogen (i.e., an increase in estrogen levels is much greater than an increase in progesterone levels). It is consistent that transgenic mice expressing HPV16 E6 and E7 (K14E6/K14E7) develop cervical cancer only when treated with physiological levels of estrogen. Using this validated mouse model, we demonstrated that estrogen receptor alpha (ERα) antagonists (e.g., raloxifene) or a progesterone receptor (PR) agonist [e.g. medroxyprogesterone acetate (MPA)] is efficient in treating cervical cancer. Cervical cancer recurs after raloxifene therapy, and recurring disease remains sensitive to raloxifene. The present study investigates whether cervical cancer recurs after stopping MPA treatment. Consistent with our prior results, K14E6/K14E7 mice (7 of 7) developed cervical cancer after 6-month estrogen treatment (initial cancer), which regressed in 14 of 14 mice upon 2-month MPA treatment (i.e., complete response). When the mice were re-treated for 2 months with estrogen after MPA therapy, cervical cancer was observed in 6 of 6 mice (100%). As a control, a group of mice were left untreated for first 6 months, and then treated with MPA for 2 months followed by 2-month estrogen treatment. We defined cervical disease in this group as newly arising disease. Cancer incidence in this group (25%; 4 of 16 mice) was significantly lower. These results indicate that cervical cancer recurs if MPA treatment is discontinued. Interestingly, recurrence was also observed in 8 of 8 mice without readministration of estrogen, indicating that recurring cancers are independent of exogenous estrogen (we do not know whether they depend on endogenous estrogen). Strikingly, when mice bearing recurring cancers were re-treated with MPA, cancer incidence (100%, 5 of 5 mice) and cancer multiplicity remained similar to a control group, and moderate reduction in cancer size was observed. These results indicate that recurring cervical cancers acquired resistance to PR agonist therapy. This resistance was not due to loss of PR because PR status in recurring cancers was similar to that in initial cancers. Further study is warranted to determine a mechanism of therapy resistance in this mouse model, which is anticipated to facilitate development of a more efficient therapy for the disease.

Citation Format: Fabiola Mehta, Sang-Hyuk Chung. Recurrence and hormone therapy resistance of cervical cancer in a transgenic mouse model. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B05.