Reproductive development and tumorigenesis are the two main topics in reproductive research. Enhancer of zeste (EZH2), a core component of Polycomb Repressive Complexes 2, possesses histone methyltransferase activity that catalyzes the trimethylation of lysine 27 of histone H3. It has been shown that EZH2 is involved in epithelial to mesenchymal transition (EMT), a key event in development and carcinogenesis. However, the role of EZH2 in the uterus and endometrial cancer remains poorly defined. In Aim 1, we generated a mouse model harboring conditional deletion of Ezh2 in the uterus. The uterine epithelium became stratified and further developed into endometrial hyperplasia in this mouse model. Fertility defects accompanied by altered uterine growth and function were also found in the Ezh2 conditional knockout (Ezh2 cKO) mice. Findings suggest EZH2 protects epithelial integrity partially by inhibiting the differentiation of basal-like cells and preventing epithelial stratification. To study the role of Ezh2 in endometrial cancer development, we generate a mouse model with double deletion of both Ezh2 and Pten in Aim 2. Compared to Ptend/d mice, reduced tumor burdens were observed in the Ptend/d; Ezh2d/d mice. However, the deletion of Ezh2 induced altered immune response, enhanced inflammation, and exacerbated epithelial stratification, leading to unfavorable disease outcomes. These results suggest EZH2 plays dual roles in endometrial cancer development. Aim 3 of the dissertation was to study mechanism underlying the development of testicular granulosa cell tumors (TGCTs), a type of rare tumor in the testis. A mouse model with constitutively activative transforming growth factor beta receptor 1 (TGFBR1) in the testis was generated. The development of sex cord-stromal tumor, resembling TGCT, led to overproliferation in Sertoli cells and defective spermatogenesis. The testicular tumors were identified as TGCTs for the positive staining of granulosa cell markers including INHA, FOXO1, and FOXL2 essential for ovarian granulosa cell differentiation and functions. Thus, Aim 3 uncovered an oncogenic role of TGF? signaling in the testis. In summary, these studies have identified mechanisms of reproductive development and tumorigenesis and will potentially guide the development of targeted therapy for pregnancy failure and tumors in the reproductive system.
