Down-regulation of transforming growth factor-β type II receptor (TGF-βRII) protein and mRNA expression in cervical cancer

Estrogen-induced carcinogenesis was accompanied by an increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-E7 mice. TGF-β2 mRNA and protein levels increased in K14-E7 transgenic mice as compared with nontransgenic mice and further increased after hormone-treatment in both nontransgenic and transgenic mice. In contrast, TGF-βRII mRNA and protein levels were decreased in K14-E7 transgenic mice compared to nontransgenic mice and these levels were further decreased after hormone treatment in transgenic mice. We also observed that c-myc mRNA levels were high in K14-E7 mice irrespective of estrogen treatment and were increased in estrogen-treated nontransgenic mice. Finally we found that p15 mRNA levels were not increased in K14-E7 mice.These results suggest that the synergy between estrogen and E7 in inducing cervical cancer may in part reflect the ability of both factors to modulate TGF-β signal transduction.Cervical cancer (CC) is one of the most frequent cancers affecting women worldwide and is an important public health problem for adult women in developing countries [1].Infection with HR-HPV types, in particular HPV16 and HPV18, is a crucial step in the etiology of CC [2,3]. The oncogenic process is mainly driven by the viral proteins E6 and E7, which inactivate tumor suppressor gene products p53 and pRB, respectively. Despite infection with HR-HPV subtypes, most precancerous cervical lesions termed cervical intraepithelial neoplasia (CIN) do not progress to in situ or invasive carcinoma implicating either environmental or genetic cofactors in those rare cases where progression occurs [4]. For example, both cigarette smoking and genetic predisposition have been linked to cervical carcinogenesis associated with HR-HPV [5]. Another cofactor that has been repeatedly associated with cervical neoplasia is exposure to estrogen [6]. This raises the important question of which genetic or biologic