gms | German Medical Science

Endometrial Carcinoma (EnCa) is the most common invasive gynaecologic cancer in postmenopausal women in Europe and USA. The etiology for EnCa involves both genetic and hormonal changes, which in most cases involves a prior endometrial hyperplasia stage. The Estrogen receptor (ER) positive subtype endometrioid adenocarcinoma represents over 80% of EnCa cases. The causal relationship between hormone replacement therapies and EnCa has been confirmed since the first report was published in 1975. An increase of relative EnCa risk with selective estrogen receptor modulators (SERMs), like Tamoxifen used for breast cancer prevention was 1.5-4.0 fold and for adjuvant trials was found to be 1.8-6.4 fold. Results from Realtime-PCR for ERα showed the highest expression in EnCa > hyperplasia > endometrial polyps > control endometrium; for ERβ no variations between the different tissues were found. The human endogenous retroviral (HERV)-W envelope gene, Syncytin, was found significantly increased at the mRNA and protein levels in EnCa and their pre-stages, as compared to patient matched control Endometrium. Interestingly, endometrial hyperplasia and polyps from patients treated previously with Tamoxifen showed the highest Syncytin expression. Cell culture experiments of primary EnCa cells and cell lines demonstrated an induction of Syncytin and cell proliferation in the presence of Estradiol, which could be abrogated with Syncytin-siRNA. Similar cell culture experiments are in progress with Tamoxifen and 4-OH-Tamoxifen. Two possible molecular causes for the Syncytin stimulation by Tamoxifen are being currently tested: 1) A direct binding of Tamoxifen-ERα-complexes to the new estrogen receptor response element in the LTR of HERV-W, or 2) through an indirect stimulation of ERα via induction of ER-activators, like SRC1 and AIB1, and concomitant reduction of ER-repressors, like NCOR and SMRT. These results show that Syncytin could play a role in EnCa tumor staging in cases of Tamoxifen induced hyperplasia.