Elucidating Isoform Specific Roles of Calpain-1 and Calpain-2 in Breast Cancer
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Authors
Shapovalov, Ivan
Date
Type
thesis
Language
eng
Keyword
Calpain , Triple Negative Breast Cancer , Metastasis
Alternative Title
Abstract
Breast 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.
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution 3.0 United States
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution 3.0 United States