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

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.

Hypoxia-Inducible Factor-1α (HIF-1α) Promotes Hypoxia-Induced Invasion and Metastasis in Ovarian Cancer by Targeting Matrix Metallopeptidase 13 (MMP13)

“…MMP13 level in ascitic fluid was seemed to be associated with shorter survival. Thus, MMP13 could be a potential prognostic factor and plays an important role in ovarian cancer metastasis [29,30].…”

MEK5 promotes lung adenocarcinoma

“…MEK5 and ERK5 protein activation and expression were evaluated by Western blotting in 23 LUAD samples and 11 nontumoral lung samples (nine of them corresponding to counterparts of the same LUAD patient). Constitutively active MEK5, identified using an anti-pMEK5 antibody [11], was present in tumour samples whereas no pMEK5 was detected in normal lung tissue (figure 1i). Consequently, pERK5 was observed in the LUAD samples but not in their nontumoral counterparts.…”

Truncated O-glycosylation in metastatic triple-negative breast cancer reveals a gene expression signature associated with extracellular matrix and proteolysis

“…These enzymes degrade various proteins in the ECM allowing the cells to invade surrounding tissues and form new blood vessels that support tumor growth 42 , 43 . In addition, MMPs can target receptors on the surface of tumor cells, activating pathways that foster proliferation, suppress apoptosis, stimulate metabolic changes or induce EMT 44 – 46 . Several DEGs that were functionally linked to the GO term metallopeptidase activity (GO:0008237) participate in the development of BC and promote tumor progression and angiogenesis, such as mmp1a 47 , mmp9 48 , mmp13 49 and mmp15 50 .…”