Elucidating Isoform Specific Roles of Calpain-1 and Calpain-2 in Breast Cancer

dc.contributor.authorShapovalov, Ivanen
dc.contributor.departmentPathology and Molecular Medicineen
dc.contributor.supervisorGreer, Peter A.
dc.degree.grantorQueen's University at Kingstonen
dc.description.abstractBreast cancer is the most frequently diagnosed women’s cancer in Canada. Average patient survival rates are high, but they are significantly reduced for those patients whose cancer reaches stage IV – metastatic disease. This study investigated the roles of calpain-1 and calpain-2 in metastatic breast cancer. Genetic knockout of CAPN1, CAPN2, and CAPNS1 genes allowed us to analyze the functions of these two calpain isoforms in the MDA-MB-231 triple negative breast cancer model cell line and to determine which isoform is responsible for the CAPNS1-knockdown related cancer cell phenotypes seen previously. We used the panel of knockout and rescue cell lines for in vitro studies and showed that both calpain isoforms play roles in protective effects against select chemotherapeutics, suggesting that calpain inhibition could enhance the efficacy of these commonly used breast cancer therapeutics. We also showed that genetic disruption of calpain-1 reduces the in vitro cell migration rate on collagen substrates. Our in vivo studies provide evidence that calpain-1 and calpain-2 have essential non-redundant roles in the metastatic process, suggesting that inhibition of either isoform could have therapeutic benefits by reducing the metastatic potential of breast cancer. I also discuss future studies aimed at identification and characterization of calpain-1 and calpain-2 specific physiological substrates with mechanistic relevance to the observed phenotypes and describe a biosensor to screen for allosteric inhibitors of calpain-1 and calpain-2.en
dc.embargo.termsThe reason for restricting the thesis is to protect rights to the structure of biosensor constructs described in the thesis which will be used in a future application for a patent arising from the research.en
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
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dc.rightsAttribution 3.0 United States*
dc.subjectTriple Negative Breast Canceren
dc.titleElucidating Isoform Specific Roles of Calpain-1 and Calpain-2 in Breast Canceren
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