Author ORCID Identifier
Date of Graduation
8-2022
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Filippo Giancotti
Committee Member
Pierre McCrea
Committee Member
Nicholas Navin
Committee Member
Andrea Viale
Committee Member
Giannicola Genovese
Committee Member
Florian Muller
Abstract
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.
Keywords
Matrix stiffness, Mechanotransduction, Integrin signaling, FAK, Src, breast cancer, HER2, tumor growth, metastasis