Abstract A29: YAP interacts with the ERBB signaling pathway to control ovarian surface epithelial cell tumorigenesis.

Abstract

Abstract Introduction: The Hippo signaling pathway controls organ size and inhibits tumorigenesis through a kinase cascade that leads to the phosphorylation of the transcriptional co-activator Yes-associated protein 1 (YAP1, more commonly referred to as YAP). Recent studies have shown that YAP may play a role in the progression of ovarian cancer. However, current reports considering the relationships between YAP expression and clinicopathological outcomes in ovarian cancer are inconsistent. Additionally, the role and functional mechanism of YAP on ovarian tumorigenesis and ovarian cancer progression are not fully understood. Aims: The aims of the present study are to examine the role of YAP in the tumorigenesis of ovarian surface epithelial cells, and to uncover the molecular mechanisms underlying YAP regulation of OSE malignant transformation. Methods: We used a large cohort of ovarian cancer patient samples, an ovarian tissue-specific YAP-overexpression mouse model, and a series of unique cellular models to address above questions. Results: Immunohistochemical analysis using a large cohort of patient samples indicated that YAP expression is associated with poor clinical outcomes in ovarian cancer patients. Overexpression of wild-type YAP or constitutively active YAP in immortalized human ovarian surface epithelial cells (HOSE) induced anchorage-independent growth of these cells in a soft agar assay and tumorigenesis in a xenograft mouse model, suggesting that YAP is sufficient to induce transformation of immortalized human OSEs. To confirm the pathological relevance of our findings, we created an ovarian tissue-specific YAP overexpression mouse model by breeding AMHR2-cre mice to ROSA26-rtTA mice and tetO-YAPS127A mice. The created AMHR2-Cre-rtTA-tetO-YAPS127A mice specifically express YAPS127A (constitutively active YAP) in ovarian tissues once these mice are treated with doxycycline (Dox). We found that AMHR2-induced ovarian tissue specific expression of YAPS127A, which led to drastic neoplasia of ovarian surface epithelial (OSE) cells in AMHR2-Cre-rtTA-tetO-YAPS127A mice after induction with Dox for 3 weeks. In addition, our mechanistic studies indicated that activation of YAP in human OSE cells induced expression of EGFR, ERBB3, HBEGF, NRG1 and NRG2 both in vitro and in vivo. Intriguingly, the activated ERBB signaling in turn suppressed the Hippo pathway and activated YAP protein. Conclusion: Our results demonstrate the existence of a NRGs & HBEGF/ERBBs/YAP/NRGs&HBEGF autocrine loop that may play a critical role in regulating the development and progression of ovarian cancer. Our study clearly indicates that combined targeting of ERBB and the Hippo/YAP pathways represents a novel strategy for treatment of ovarian cancer. Citation Format: Chunbo He, Xiangmin LV, John S. Davis, Wang Cheng. YAP interacts with the ERBB signaling pathway to control ovarian surface epithelial cell tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A29.