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 control of endometrial cell proliferation and differentiation we have generated cell lines derived from rat endometrium by expressing the immortalizing oncogenes adeno E1A or SV40 large T antigen. These lines are positive for mesenchymal markers and contain very few characteristic epithelial proteins. Cell lines expressing a temperature-sensitive mutant of SV40 T antigen exhibit a temperature-dependent morphology and growth behavior, but do not manifest an epithelial phenotype at the non-permissive temperature. Cell lines additionally infected with retroviral vectors carrying the v-Ha-ras oncogene (p21rasArg-12) no longer express collagen type III and recover part of their epithelial potential by expressing cytokeratins and/or cadherin E. Some of these cells also express characteristic decidual marker proteins such as desmin, whereas others express glandular epithelial markers such as uteroglobin. Uteroglobin mRNA levels in these cells are increased by glucocorticoids. The parental temperature-sensitive cells do not contain progesterone receptor but become positive for progesterone receptor at the permissive temperature after infection with the v-Ha-ras-expressing retrovirus. Our results indicate that there is a fluent transition and overlapping 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 appears to act on the differentiation pathway at an early step prior to the distinction between decidual and glandular epithelial lineage.