CHRONIC ESTROGEN-INDUCED CERVICAL AND VAGINAL SQUAMOUS CARCINOGENESISIN HUMAN PAPILLOMAVIRUS TYPE-16 TRANSGENIC MICE

High-risk human papillomaviruses (HPVs), including type 16, have been identified as factors in cervical carcinogenesis, However, the presenc e and expression of the virus per se appear to be insufficient for car cinogenesis. Rather, cofactors most likely are necessary in addition t o viral gene expression to initiate neoplasia, One candidate cofactor is prolonged exposure to sex hormones. To examine the possible effects of estrogen on HPV-associated neoplasia, we treated transgenic mice e xpressing the oncogenes of HPV16 under control of the human keratin-14 promoter (K14-HPV16 transgenic mice) and nontransgenic control mice w ith slow-release pellets of 17 beta-estradiol, Squamous carcinomas dev eloped in a multistage pathway exclusively in the vagina and cervix of K14-HPV16 transgenic mice, Estrogen-induced carcinogenesis was accomp anied by an incremental increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous ep ithelium of K14-HPV16 mice, Expression of the HPV transgenes in untrea ted transgenic mice was detectable only during estrus; estrogen treatm ent resulted in transgene expression that was persistent but not furth er upregulated, remaining at low levels at all stages of carcinogenesi s, The data demonstrate a novel mechanism of synergistic cooperation b etween chronic estrogen exposure and the oncogenes of HPV16 that coord inates squamous carcinogenesis in the female reproductive tract of K14 -HPV16 transgenic mice.