Sfrp4 Modulates Emt, Cell Migration And Downstream Wnt Signalling In Epithelial Ovarian Cancer.

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Epithelial ovarian cancer is the fifth most common cause of death from all female cancers. This poor overall prognosis results in part from late diagnosis and a current lack of targeted therapy, stemming from the current limited understanding of the initiating events of ovarian carcinogenesis. There is a critical need for the identification of ovarian cancer pathways and targets to aid in diagnosis, as prognostic indicators and as targets for novel therapies. Wnt signalling is essential for crucial components of carcinogenesis and metastasis including differentiation, polarity, migration, adhesion and survival, and hence the role of Wnt signalling in human cancer is increasingly being investigated along with strategies to target pathway components. The Wnt pathway is regulated at multiple levels, with the Wnt antagonists or “gatekeeper proteins” receiving attention in recent years, due to their frequent loss in cancer. Secreted frizzled receptor proteins (SFRPs) are extracellular inhibitors of Wnt signalling that act by binding directly to Wnt ligands or Frizzled receptors, and have been shown to function as tumour suppressors in other cancer types. We have previously shown that one of these inhibitors, SFRP4, is progressively lost in more aggressive ovarian cancer phenotypes, such as Type II cancers (Jacob et al, 2011). Furthermore, patients lacking SFRP4 expression had a poorer prognosis than those expressing SFRP4. Here, we investigated the functional consequences of SFRP4 modulation in ovarian cancer cell lines. Re-expression of SFRP4 resulted in decreased expression of downstream components of Wnt signalling, inhibition of cell migration, and inhibition of epithelial to mesenchymal transition (EMT). In parallel, knockdown of SFRP4 resulted in ovarian cells upregulating markers of EMT. These results indicate that modulation of an upstream gatekeeper of Wnt signalling can have dramatic downstream effects on ovarian cancer cell behaviour, as mediated through EMT. This raises the possibility that SFRP4 may be a suitable marker of ovarian carcinogenesis, and that targeting the Wnt signalling pathway may have potential as an ovarian cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 333. doi:1538-7445.AM2012-333