Integrin-Mediated Mechanotransduction Controls Activation of YAP and Invasive Growth of Breast Cancer
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Date of Graduation
Doctor of Philosophy (PhD)
Tumor extracellular matrix (ECM) stiffness is correlated with the aggressiveness of breast cancer. Integrin-mediated adhesion and signaling are crucial for mammary tumorigenesis and tumor progression, in which focal adhesion kinase (FAK) - Src family kinases (SFKs) serves as a hub to relay the mechanical cues from the ECM. We have investigated the mechanisms through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechanotransduction controls invasive growth of breast cancer cells in stiff matrices through activation of FAK and YAP. Mechanistic studies revealed that integrin signaling induces - via activation SFKs - tyrosine phosphorylation and inactivation of LATS1 and MOB1. The ensuing activation of YAP is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP in HER2+ breast cancer cells, suggesting that integrin-mediated mechanotransduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of Dasatinib combined with Lapatinib 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 tumor suppressive 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.
Matrix stiffness, Mechanotransduction, Integrin signaling, FAK, Src, breast cancer, HER2, tumor growth, metastasis
Available for download on Saturday, July 29, 2023