Endometrial carcinoma (EnCa) is the most common invasive gynaecologic carcinoma. Over 85% of EnCa are classified as endometrioid, expressing steroid hormone receptors and mostly involve pathological prestages. Evolutionarily occurring exogenous retroviral infections into germ lines generated human endogenous retroviruses (ERV) and represent today ∼8% of the human genome. Our research parallels similarities between placentogenesis, where ERV envelope (env) genes have essential functions, and tumorigenesis. Previously, we demonstrated that Syncytin-1 (ERVW-1 env gene) up regulation was involved in EnCa cell fusion and steroid hormone proliferation regulated by TGF-ß. Additionally, Syncytin-1 was up regulated in EnCa tissues from tamoxifen treated breast carcinoma patients. The majority of ERV env coding genes are either not present or not consistently represented on gene expression microarrays.
For the first time all 21 ERV env genes, including 19 codogenic and two env genes with premature stop codons were cloned and analysed for their absolute gene expression in 38 EnCa, 31 endometrium, 9 endometrial hyperplasia and 20 polyps. ERV env genes showed a stepwise increase of expression from the benign to malignant states. We classified env expression into three different categories. For example, EnCa demonstrated seven genes with high >200 mol/ng cDNA expression where Syncytin-1 was the highest single gene; two middle >50 mol/ng cDNA expressed (e.g. erv-3) and 12 low <50 mol/ng cDNA expressed (e.g. Syncytin-2). Overall, ERV env genes were in part similar in their expression hierarchy when compared to 34 term placentas, supporting parallel functions. Regarding tumor parameters, Syncytin-1 and Syncytin-2 were significantly up regulated in advanced stage pT2 compared to pT1b. In less differentiated EnCa Syncytin-1, erv-3, envT and envFc2 were up regulated. Using immunohistochemistry Syncytin-1, Syncytin-2 and erv-3 specifically localized to glandular epithelial cells of polyps, hyperplasia and EnCa. As noted in patient-matched EnCa compared to endometrium, increased Syncytin-1 expression correlated with ERVW-1 5’long terminal repeat (LTR) hypomethylation, including the ERE and CRE overlapping MeCP2 sites. This hypomethylation state was similar to human placental cytotrophoblasts.
Functional analyses showed 10 additional env genes also regulated by methylation in EnCa cell lines. Co-transfection of an estrogen receptor (ER) negative EnCa cell line with an ERα and ERVW-1 5’LTR-luciferase reporter constructs, resulted in increased activity following treatment with estradiol and tamoxifen, which was suppressed by methylation.
Reactivated and overexpressed ERV env genes could serve to promote tumorigenesis of pathological pre-stages and EnCa. A comparative model involving ERV in placentogenesis versus EnCa is presented.
Citation Format: Pamela L. Strissel, Matthias Ruebner, Falk Thiel, David Wachter, Arif B. Ekici, Florentine Koppitz, Matthias W. Beckmann, Reiner Strick. Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: emergence of new molecular targets. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4800. doi:10.1158/1538-7445.AM2013-4800