Role of Oocyte Loss in Ovarian Surface Mesothelial Cell Transformation

Three Specific Aims (SA) were proposed to test in mice if accelerated oocyte loss caused by Bclw deficiency or Bax gain-of-function drives ovarian surface mesothelial cell (OSMC) transformation: 1) characterize preneoplastic changes in OSMC of Bclw(-/-)1 mice with increasing age; 2) determine if disruption of the gene encoding Bax rescues the compromised oocyte survival and the OSMC transformation phenotype in aging Bclw(-/-) mice; and, 3) test if targeting overexpression of Bax to only growing oocytes accelerates oocyte depletion and causes OSMC transformation. To date, we have confirmed the occurrence of OSMC transformation in aging Bclw mutants, but there is no progression to invasive carcinoma by 20+ months of age (SA 1). Inactivation of Bax restores the compromised oocyte endowment in neonatal Bclw mutants to normal, but this protective effect on the oocyte pool is lost in young adult females (SA2). We have constructed a zp3-Bax minigene and have begun to generate transgenic mice expressing Bax only in growing oocytes (SA 3). Finally, we have shown in another mouse model that accelerated oocyte loss is directly involved in ovarian tumorigenesis. In addition, we have demonstrated a direct growth inhibitory effect of oocytes on human ovarian cancer cells in vitro.