Onset of direct 17-β estradiol effects on proliferation and c-fos expression during oncogenesis of endometrial glandular epithelial cells

Abstract In normal endometrial glandular epithelial cells (GEC), 17β-estradiol (E 2 ) enhances proliferation and c- fos expression only in the presence of growth factors. On the contrary, growth factors are not required for the E 2 effects in cancerous cells. Thus, a repression of E 2 action could exist in normal cells and be turned off in cancerous cells, allowing a direct estrogen-dependent proliferation. To verify this hypothesis, we established immortalized and transformed cell models, then investigated alterations of E 2 effects during oncogenesis. SV40 large T-antigen was used to generate immortalized GEC model (IGEC). After observation of telomerase reactivation, IGEC model was transfected by activated c-Ha- ras to obtain transformed cell lines (TGEC1 and TGEC2). The phenotypic, morphological, and genetic characteristics of these models were determined before studying the E 2 effects. In IGEC, the E 2 action on proliferation and c- fos expression required the presence of growth factors, as observed in GECs. In TGECs, this action arose in the absence of growth factors. After IGEC transformation, the activation of ras pathway would substitute the priming events required for the release of repression in GEC and IGEC and thus permit direct E 2 effects. Our cell models are particularly suitable to investigate alterations of gene regulation by E 2 during oncogenesis.