Regulation of the prometastatic neuregulin-MMP13 axis by SRC family kinases: therapeutic implications.

Ana Orive‐Ramos,Atanasio Pandiella,Juan Carlos Montero,Alberto Ocaña,Samuel Seoane

doi:10.1002/1878-0261.12145

Abstract

Metastatic dissemination of tumor cells is responsible for the fatal outcome of breast cancer. Therefore, understanding the mechanisms involved in dissemination is essential for the development of new therapeutic strategies to prevent metastasis. One mechanism involved in metastatic dissemination of breast cancer cells is dependent on control of the production of matrix metalloproteinases by the neuregulins (NRGs). The NRGs are polypeptide factors that act by binding to the ErbB/HER subfamily of receptor tyrosine kinases. NRG‐mediated activation of HER receptors causes an increase in the production of metalloprotease 13 (MMP13, also termed collagenase‐3), which facilitates metastatic dissemination of breast tumors. In this context, we aimed to explore whether the clinically approved tyrosine kinase inhibitor dasatinib was able to neutralize this mechanism of metastatic dissemination. Here, we show that dasatinib restricted NRG‐induced MMP13 upregulation, both in vitro and in vivo, and in vivo metastatic dissemination of breast cancer cells. Chemical proteomics studies showed that the main cellular targets of dasatinib were SRC family kinases (SFKs). Moreover, genetic studies showed that knockdown of SRC or YES strongly inhibited NRG‐induced MMP13 upregulation in vitro. Mechanistically, dasatinib treatment or knockdown of SRC also inhibited ERK1/2 kinases in vitro, which were required for NRG‐induced MMP13 upregulation. These results open the possibility of clinically exploring the antitumoral action of dasatinib in those tumors in which the NRG–MMP13 signaling axis may play a relevant role in the control of tumor cell dissemination.

Highlights

The neuregulins (NRGs), a group of polypeptides that belong to the epidermal growth factor family of ligands (Montero et al, 2008), were initially identified while searching for ligands able to activate the HER2 transmembrane tyrosine kinase (Holmes et al, 1992; Peles et al, 1992)
Dasatinib treatment or knockdown of SRC inhibited ERK1/2 kinases in vitro, which were required for Neuregulin b2 (NRG)-induced matrix metalloproteinase 13 (MMP13) upregulation
We explored the action of dasatinib on NRG-induced upregulation of MMP13 levels using several cell lines belonging to different breast cancer subtypes

Summary

Introduction

The neuregulins (NRGs), a group of polypeptides that belong to the epidermal growth factor family of ligands (Montero et al, 2008), were initially identified while searching for ligands able to activate the HER2 transmembrane tyrosine kinase (Holmes et al, 1992; Peles et al, 1992). The interest in the identification of activators of HER2 was promoted by the finding that this membrane protein was overexpressed in a subset of patients with breast cancer, and such overexpression correlated with metastatic dissemination of the disease and poor patient outcome (Slamon et al, 1987). While NRGs were initially isolated by their ability to activate HER2, they do not bind to HER2 (Peles et al, 1993; Sliwkowski et al, 1994). Abbreviations Luc, luciferase; MMP13, matrix metalloproteinase 13; NRGs, neuregulins; SFKs, SRC family kinases.

Objectives

Methods

Results

Discussion

Conclusion