Abstract 1230: Wnt5a-dependent induction of senescence suppresses epithelial ovarian cancer

Abstract

Abstract Epithelial Ovarian Cancer (EOC) remains the most lethal gynecological malignancy in US and is the fifth leading cause of cancer deaths among American women. Thus, there is an urgent need to understand the etiology of EOC to develop novel therapies for this disease. Wnt5a is classified as a non-canonical Wnt ligand. Here, we demonstrated that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOC compared with either normal ovarian surface epithelial cells (p=0.039) or fallopian tube epithelial cells (p<0.001). Importantly, expression of Wnt5a in primary human EOC inversely correlates with tumor stage (p=0.003) but not tumor grade (p=0.086). Interestingly, Wnt5a expression is significantly lower in Type II high-grade serous EOC compared to Type I EOC that includes low-grade serous, mucinous, clear cell and endometrioid subtypes of EOC (p=0.005). In addition, we discovered that hypermethylation of promoter CpG island contributes to Wnt5a downregulation in human EOC cells. Significantly, restoration of Wnt5a expression in human EOC cells promoted senescence of EOC cells and resulted in a dramatic decrease in cell proliferation both in vitro and in vivo in an orthotopic model of EOC in the ovary of SCID mice. Mechanistically, Wnt5a inhibited canonical Wnt/beta-catenin signaling and resulted in the activation of senescence-promoting histone repressor A/PML pathway. In summary, we show that Wnt5a is often expressed at lower levels in primary human EOC and Wnt5a expression suppresses the growth of EOC cells by triggering senescence through antagonizing canonical Wnt signaling. Our data imply that the cell of origin between Type I and Type II EOC is different. These results also suggest that loss of Wnt5a expression is a putative marker of EOC and that non-canonical Wnt signaling is a potent target for developing novel EOC therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1230. doi:10.1158/1538-7445.AM2011-1230