Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling

Gina L. Zoratti, Lauren M. Tanabe, Fausto A. Varela, Andrew S. Murray, Christopher Bergum, Éloïc Colombo, Julie E. Lang, Alfredo A. Molinolo, Richard Leduc, Eric Marsault, Julie Boerner and Karin List ()
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Gina L. Zoratti: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
Lauren M. Tanabe: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
Fausto A. Varela: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
Andrew S. Murray: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
Christopher Bergum: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
Éloïc Colombo: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Julie E. Lang: Norris Comprehensive Cancer Center, University of Southern California
Alfredo A. Molinolo: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Richard Leduc: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Eric Marsault: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Julie Boerner: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
Karin List: Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years because of its consistent dysregulation in human epithelial tumours, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumour formation and blunted tumour growth. The abated tumour growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase-deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signalling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer.

Date: 2015
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DOI: 10.1038/ncomms7776

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