Abstract PR04: Integrin-mediated mechano-transduction controls HER2 oncogenic signaling and activation of YAP in breast cancer

Abstract

Abstract Integrin-mediated adhesion and signaling via focal adhesion kinase is required for mammary tumorigenesis in the PyMT mouse model. Moreover, PTK2 encoding FAK is amplified in a substantial fraction of human breast cancers. We have investigated the mechanism through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechano-transduction controls invasive growth in stiff 3D matrices through activation of YAP/TAZ. Mechanistic studies revealed that integrin signaling induces—via activation of FAK and Src family kinases (SFKs) —tyrosine phosphorylation and inactivation of LATS. The ensuing activation of YAP/TAZ is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP/TAZ in HER2+ breast cancer cells, suggesting that integrin-mediated mechano-transduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of dasatinib significantly increases the efficacy of HER2 inhibition in the MMTV-Neu mouse model of HER2+ breast cancer. These findings reveal a major mechanism through which the Hippo pathway is disabled in breast cancer and suggest that targeting HER2 and SFKs simultaneously may be a rational strategy in selected cases of breast cancer. This abstract is also being presented as Poster A22. Citation Format: Shimin Wang, Young-Mi Kim, Ralph Garippa, Larry Norton, Filippo G. Giancotti. Integrin-mediated mechano-transduction controls HER2 oncogenic signaling and activation of YAP in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr PR04.