EXPRESSION OF EPITHELIAL PHENOTYPE IS ENHANCED BY V-HA-RAS IN RAT ENDOMETRIAL CELLS IMMORTALIZED BY SV40-T ANTIGEN

To study the interplay of steroid hormones and oncogenes in the contro l of endometrial cell proliferation and differentiation we have genera ted cell lines derived from rat endometrium by expressing the immortal izing oncogenes adeno EIA or SV40 large T antigen. These lines are pos itive for mesenchymal markers and contain very few characteristic epit helial proteins. Cell lines expressing a temperature-sensitive mutant of SV40 T antigen exhibit a temperature-dependent morphology and growt h behavior, but do not manifest an epithelial phenotype at the non-per missive temperature. Cell lines additionally infected with retroviral vectors carrying the v-Ha-ras oncogene (p21ras(Arg-12)) no longer expr ess collagen type III and recover part of their epithelial potential b y expressing cytokeratins and/or cadherin E. Some of these cells also express characteristic decidual marker proteins such as desmin, wherea s others express glandular epithelial markers such as uteroglobin. Ute roglobin mRNA levels in these cells are increased by glucocorticoids. The parental temperature-sensitive cells do not contain progesterone r eceptor but become positive for progesterone receptor at the permissiv e temperature after infection with the v-Ha-ras-expressing retrovirus. Our results indicate that there is a fluent transition and overlappin g between mesenchymal, glandular epithelial and decidual phenotypes of endometrial cells, suggesting that these three cell types are derived from the same stem/precursor cells. The v-Ha-ras oncogene product app ears to act on the differentiation pathway at an early step prior to t he distinction between decidual and glandular epithelial lineage.