Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications. Issue 12 (31st October 2017)

• Record Type: Journal Article
• Authors: Orive‐Ramos, Ana; Seoane, Samuel; Ocaña, Alberto; Pandiella, Atanasio; Montero, Juan Carlos
• Is Part Of: Molecular oncology. Volume 11:Issue 12(2017)
• Page Start: 1788
• Page End: 1805
• Publication Date: 2017-10-31
• Subjects: breast cancer dissemination -- dasatinib -- MMP13 -- neuregulin -- SRC; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12145
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : Understanding the mechanisms involved in breast cancer dissemination is essential for the development of new therapeutic strategies to prevent metastasis and improve patient outcome. Our studies describe that the prometastatic neuregulin–MMP13 axis is regulated by SRC family kinases. Moreover, the clinically approved tyrosine kinase inhibitor dasatinib was found to restrict NRG‐induced MMP13 upregulation and metastatic dissemination of breast cancer cells.