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Nat Commun. 2015 Apr 15;6:6776. doi: 10.1038/ncomms7776.

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

Author information

1
1] Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [2] Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [3] Cancer Biology Graduate Program, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 110 E. Warren Avenue, Suite 2215, Detroit, Michigan 48201, USA.
2
Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA.
3
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Av Nord, Sherbrooke, Quebec J1H 5N4, Canada.
4
Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, 1510 San Pablo Street, Suite 412, Los Angeles, California 90033, USA.
5
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, Maryland 20892, USA.
6
Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA.

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.

PMID:
25873032
PMCID:
PMC4749267
DOI:
10.1038/ncomms7776
[Indexed for MEDLINE]
Free PMC Article

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