Calpain-1 and Calpain-2 Promote HER2/NEU Tumorigenesis and Independently Promote Metastasis in Triple Negative Breast Cancer
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Authors
MacLeod, James
Date
Type
thesis
Language
eng
Keyword
calpain , HER2 , NEU , triple negative breast cancer , breast cancer
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Abstract
Calpains are a family of calcium activated cysteine proteases. Calpain-1 and calpain-2 are obligate heterodimers composed of isoform specific catalytic subunits (encoded by capn1 and capn2, respectively) coupled with the common, shared regulatory subunit calpain small subunit 1 (encoded by capns1). Here, we report a role for these calpains in promoting spontaneous tumor onset in a model of human HER2+ breast cancer, as well as a requirement for these calpains for tumor viability in an orthotopic engraftment model. Furthermore, we demonstrated that knockout of capns1 correlated with enhanced sensitivity to the chemotherapeutic doxorubicin, the EGFR/HER2 inhibitor lapatinib, and sustained MAPK signaling in response to EGF. In a model of triple-negative breast cancer we demonstrate that CRISPR/CAS9-mediated knockout of calpain-1 (capn1) or calpain-2 (capn2) independently attenuated metastatic colonization in vivo, and that knockout of either isoform was associated with attenuated production of MMP-9. Collectively, our results suggest a pro-tumorigenic role for calpain-1/2 in both HER2+ and triple-negative breast cancer, which provides preclinical evidence in support of combining calpain inhibitors with commonly used therapeutic drugs.
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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.