A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development

Abstract : Transforming growth factor beta (TGFB) signaling regulates key reproductive events via TGFBR1/TGFBR2. To determine potential effect of overactivation of TGFB signaling in the oocyte, we generated a mouse model containing a constitutively active TGFBR1 using growth differentiation factor 9 (Gdf9)-Cre (i.e., TGFBR1-gCA). Follicle counting demonstrated that the number of primordial, primary, and secondary follicles was reduced in TGFBR1-gCA ovaries compared with controls at P7. Concomitantly, abnormal follicle structures were detected in TGFBR1-gCA ovaries, evidenced by INHA staining. These results suggest that sustained activation of TGFBR1 using Gdf9-Cre disrupts folliculogenesis via affecting ovarian reserve and follicle growth/development. Apoptosis analysis using ovaries at critical timepoints during follicular development did not reveal alteration of oocyte apoptosis in TGFBR1-gCA ovaries. Immunostaining was performed to determine the molecular identify of the tumors. The results showed that ovarian tumor tissues from TGFBR1-gCA mice were positive for granulosa cell markers FOXL2, INHA, and FOXO1, supporting the formation of granulosa cell tumors in these mice. In the ovary culture system, SB-505124 seemed to improve follicle development in TGFBR1-gCA ovaries. Therefore, sustained activation of TGFBR1 using Gdf9-Cre leads to the development of ovarian neoplasms reminiscent of granulosa cell tumors.