Project 172176

Epithelial ovarian cancer is associated with a high death rate, killing more than 17,000 women each year in North America. A lack of means to detect the disease at early stages, coupled with the absence of clearly identifiable symptoms of disease onset results in the majority of cases being diagnosed at advanced stages. Although improvements in chemotherapeutic treatment of this disease have occurred, the gains in life expectancy have been modest and the overall 5-year survival rate of advanced disease remains below 30%. A better understanding of disease progression based upon identified risk factors will facilitate discovery of molecular markers of early disease/predisposition and of needed therapeutic targets to effectively manage recurrent, drug-resistant disease. Androgen action has been implicated in ovarian cancer progression. Studies from our laboratory have indicated that androgens alter the growth-inhibitory action of TGFbeta, a growth factor present in the ovary and elevated in ovarian cancer. However, TGFbeta also acts to promote cancer cell spread and invasion. Our studies have identified a novel protein, Veph1, up-regulated by androgen treatment that interacts with members of the TGFbeta signaling pathway. We have also found that VEPH1 is expressed at higher levels in more aggressive ovarian cancer cells. Our preliminary data demonstrate that Veph1 blocks TGFbeta induced gene expression in a promoter-specific fashion. Moreover, we have found that Veph1 interacts with Smurf1, a protein implicated in promoting a more invasive cell. The proposed experiments will establish the role of VEPH on TGFbeta signaling in the context of ovarian cancer and will test whether it may mediate the impact of androgen in this disease.