Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene

Abstract

The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer. Cancer Res; 70(21); 8517-25. ©2010 AACR.

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

“…Huang et al reported that knockdown of YAP significantly increased EGFRI erlotinib sensitivity in ovarian cancer cell lines that express little or no TAZ (21). In addition, knockdown of YAP in ovarian cancer cell lines that express both YAP and TAZ only led to a very moderate effect on cancer cell growth or drug sensitivity (22,23). Here, we have shown that knockdown of TAZ in breast cancer cell lines that express little or no YAP, such as BT-549 cells, increased EGFRI sensitivity; however, for breast cancer cell lines that express both YAP and TAZ, such as MDA-MB-231 cells, knockdown of TAZ may not help improve sensitivity of EGFRI treatment.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…However, sustained YAP overexpression eventually leads to formation of tumors characteristic of hepatocellular carcinoma (HCC) (Dong et al, 2007). Furthermore, genomic amplification and elevated expression and nuclear localization of YAP has been observed in human cancers (Overholtzer et al, 2006;Zender et al, 2006;Dong et al, 2007;Zhao et al, 2007;Steinhardt et al, 2008;Hall et al, 2010). Overexpression of TAZ has also been noted in human breast cancer samples and non-small cell lung cancer cell lines (Chan et al, 2008;Zhou et al, 2011b).…”

The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary

“…YAP, a mammalian homolog of Drosophila Yorkie), a key effector of this pathway, promotes EMT and cell motility in vitro (Overholtzer et al 2006;Zhao et al 2008a;Zhang et al 2009). Furthermore, abnormal YAP activity associates with poor survival of ovarian cancer patients significantly (Hall et al 2010;Zhang et al 2011b). These results drew our attention to investigate roles of the Hippo pathway in cell migration.…”