Abstract
Studies using K14E6/K14E7 transgenic mice expressing E6 and E7 oncoprotein of human papillomavirus type 16 (HPV16) have demonstrated that estrogen (E2) is required for the genesis and growth of cervical cancer. Our prior study using the same mouse model has showed that progestin drug medroxyprogesterone acetate (MPA) promotes regression of primary cervical cancer. In the present study, we use the same transgenic mouse model to determine whether the cancer recurs after MPA therapy. Cervical cancer recurred even if MPA treatment was continued. Unlike primary cervical cancer, the cancer recurred even in the absence of exogenous E2 when MPA treatment was ceased. Furthermore, recurrent cervical cancer did not fully regress upon MPA treatment. Our results support that MPA fails to completely eliminate primary cervical cancer cells and that remaining cancer cells grow independent of exogenous E2 and are refractory to MPA.
Highlights
High−risk human papillomaviruses (HPVs) are causally associated with various human cancers, among which cervical cancer is most notable [1]
These results indicated that cervical cancer and cervical intraepithelial neoplasia (CIN) regressed upon medroxyprogesterone acetate (MPA) treatment as previously demonstrated [23]
Cervical cancer arising in this group was considered as new disease based on prior results that, in HPV transgenic mice expressing E6 and E7, cervical cancer did not develop without exogenous E2 and was regressed by MPA [12, 23]
Summary
High−risk human papillomaviruses (HPVs) are causally associated with various human cancers, among which cervical cancer is most notable [1]. E6 and E7 viral oncoproteins are primarily responsible for the tumorigenic potential of these viruses. Among many cellular proteins interacting with these viral oncoproteins, p53 and pRb tumor suppressor are the most prominent target of E6 and E7, respectively [2]. The Pap test and prophylactic HPV vaccines are effective in preventing cervical cancer [4]. They are not readily available to most women in developing countries and women of low socio−economic status in some developed countries [5]. Current therapies for advanced or recurrent cervical cancer are not effective [6]. The development of effective therapy for cervical cancer is urgently needed
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