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

Gina L Zoratti,Andrew S Murray,Éloïc Colombo,Eric Marsault,Christopher Bergum,Fausto A Varela,Karin List,Alfredo A Molinolo,Julie Boerner,Richard Leduc,Lauren M Tanabe,Julie E Lang

doi:10.1038/ncomms7776

Abstract

Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years due to its consistent dysregulation in human epithelial tumors, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumor formation and blunted tumor growth. The abated tumor 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 signaling 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.

Highlights

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
Transgenic mammary tumour virus (MMTV)-Polyomavirus middle T (PymT) mice are predisposed to develop multifocal mammary carcinomas with tumour progression that is very similar to that seen in human breast carcinomas[23,24]
The findings that matriptase is expressed in the epithelial compartment and upregulated during carcinogenesis is in accordance with previous findings in human breast carcinomas rendering this tumour model well-suited to understand the role of matriptase in tumour progression in humans[3,5]

Summary

Introduction

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. 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. One concept in protease mechanistic research is that proteolytic modifications of targets, including activation of growth factors, are critically involved in carcinogenesis through activation of oncogenic signalling pathways. Tumour progression is characterized by a complex interplay between invading tumour cells and stromal cells, which includes paracrine interactions where growth factors secreted by stromal cells activate signalling pathways in the cancer cells. The type II transmembrane serine protease, matriptase, has been implicated in breast cancer since it was first discovered in breast cancer cell lines, and is highly expressed by the malignant cells in human breast carcinomas[1,2,3,4,5] It is currently not known whether matriptase plays a critical role in breast cancer progression. Since a key post-translational regulatory mechanism of oncogenic HGF/c-Met signalling is the proteolytic activation of pro-HGF, the identification of the critical activator(s) as potential targets for therapeutic intervention in cancer is important[22]

Methods

Results

Conclusion