Integrin-Mediated Mechanotransduction Controls Activation of Yap and Invasive Growth of Breast Cancer

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Wang, Xiaobo
• <p><a href="https://www.orcid.org/0000-0003-0397-919X" target="_blank">0000-0003-0397-919X</a></p>

Contributors dc:contributor

• Filippo Giancotti
• Pierre McCrea
• Nicholas Navin

• Matrix stiffness
• Mechanotransduction
• Integrin signaling
• FAK
• Src
• breast cancer
• HER2
• tumor growth
• metastasis
• Cancer Biology
• Cell Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1199

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2256