Oncotarget

Research Papers:

Genetic disruption of calpain-1 and calpain-2 attenuates tumorigenesis in mouse models of HER2+ breast cancer and sensitizes cancer cells to doxorubicin and lapatinib

James A. MacLeod, Yan Gao, Christine Hall, William J. Muller, Taranjit S. Gujral and Peter A. Greer _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:33382-33395. https://doi.org/10.18632/oncotarget.26078

Metrics: PDF 700 views  |   HTML 2211 views  |   ?  


Abstract

James A. MacLeod1,2, Yan Gao2, Christine Hall2, William J. Muller3, Taranjit S. Gujral4 and Peter A. Greer1,2

1Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada

2Division of Cancer Biology and Genetics, Queen’s Cancer Research Institute, Kingston, Ontario, Canada

3Rosalind and Morris Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Quebec, Canada

4Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Correspondence to:

Peter A. Greer, email: greerp@queensu.ca

Keywords: calpain; capns1; breast cancer; HER2

Received: July 22, 2018     Accepted: August 23, 2018     Published: September 07, 2018

ABSTRACT

Calpains are a family of calcium activated cysteine proteases which participate in a wide range of cellular functions including migration, invasion, autophagy, programmed cell death, and gene expression. Calpain-1 and calpain-2 isoforms are ubiquitously expressed heterodimers composed of isoform specific catalytic subunits coupled with an obligate common regulatory subunit encoded by capns1. Here, we report that conditional deletion of capns1 disrupted calpain-1 and calpain-2 expression and activity, and this was associated with delayed tumorigenesis and altered signaling in a transgenic mouse model of spontaneous HER2+ breast cancer and effectively blocked tumorigenesis in an orthotopic engraftment model. Furthermore, capns1 knockout in a tumor derived cell line correlated with enhanced sensitivity to the chemotherapeutic doxorubicin and the HER2/EGFR tyrosine kinase inhibitor lapatinib. Collectively, these results indicate pro-tumorigenic roles for calpains-1/2 in HER2+ breast cancer and provide evidence that calpain-1/2 inhibitors could have anti-tumor effects if used either alone or in combination with chemotherapeutics and targeted agents.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 26078