The majority of human cervical cancers are associated with the high-risk human papillomaviruses (HPVs). Their tumorigenic potential stems mainly from viral oncogenes E6 and E7, which are best known to inactivate p53 and pRb tumor suppressor, respectively. Epidemiological studies, however, have suggested that persistent HPV infections are not sufficient and other cofactors are necessary for the progression of the disease. Prior studies using HPV transgenic mice expressing E6 and E7 under the control of K14 promoter (K14E6/K14E7) have demonstrated the requirement of estrogen and estrogen receptor alpha (ERα) for the development of HPV-induced cervical cancer. It was also shown that inhibition of ERα is effective in both treating and preventing cervical cancer in the HPV transgenic mouse model. Another female sex hormone, progesterone, functions through the progesterone receptor (PR), which is a direct transcriptional target of ERα. PR and ERα are transcription factors, members of the nuclear receptor superfamily. We recently demonstrated that a PR agonist, medroxyprogesterone acetate (MPA), is efficient in regressing cervical cancer and cervical intraepithelial neoplasia (CIN) in vivo. This result suggests that PR has an anti-tumorigenic activity in the context of ERα-dependent cervical cancer. In the present study, we investigated whether cervical cancer recurs after stopping MPA treatment using the same mouse model. Consistent with our previous publication, all K14E6/K14E7 double transgenic mice treated with estrogen for 6 months had cervical cancer, which regressed when treated with MPA for 2 months. When the mice were re-treated for 2 months with estrogen after MPA treatment, cervical cancer was observed in all mice. Interestingly, the cancer was also present in all mice that were left untreated for 2 months after MPA treatment. These results suggest that cervical cancer recurs if MPA treatment is ceased. The mice bearing recurring cancer were treated with MPA again for 2 months. It was interesting that the cancer remained in 6 of 7 mice, although cancers deemed smaller than those recurred. Further analyses of these cancers are warranted. Taken together, we conclude that cervical cancer recurred once MPA was withdrawn and recurring cancers partially responded to MPA. It implies that MPA treatment regimen used in the study did not eliminate all cancerous cells. Our results suggest that, if translatable to women, continuation of MPA treatment will be warranted to prevent the recurrence of cervical cancer.

Citation Format: Fabiola Mehta, Salil Ojha, Sang-Hyuk Chung. Recurrence of cervical cancer following PR agonist withdrawal in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3131. doi:10.1158/1538-7445.AM2014-3131