Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications
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...
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doaj-24a2768018694eb8985ee922cb4934772020-11-25T03:50:46ZengWileyMolecular Oncology1574-78911878-02612017-12-0111121788180510.1002/1878-0261.12145Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implicationsAna Orive‐Ramos0Samuel Seoane1Alberto Ocaña2Atanasio Pandiella3Juan Carlos Montero4Instituto de Biología Molecular y Celular del Cáncer (IBMCC‐CIC) CSIC Salamanca SpainInstituto de Biología Molecular y Celular del Cáncer (IBMCC‐CIC) CSIC Salamanca SpainUnidad de Investigación Traslacional Hospital Universitario de Albacete Universidad de Castilla La Mancha Albacete SpainInstituto de Biología Molecular y Celular del Cáncer (IBMCC‐CIC) CSIC Salamanca SpainInstituto de Biología Molecular y Celular del Cáncer (IBMCC‐CIC) CSIC Salamanca SpainMetastatic 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.https://doi.org/10.1002/1878-0261.12145breast cancer disseminationdasatinibMMP13neuregulinSRC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Orive‐Ramos Samuel Seoane Alberto Ocaña Atanasio Pandiella Juan Carlos Montero |
spellingShingle |
Ana Orive‐Ramos Samuel Seoane Alberto Ocaña Atanasio Pandiella Juan Carlos Montero Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications Molecular Oncology breast cancer dissemination dasatinib MMP13 neuregulin SRC |
author_facet |
Ana Orive‐Ramos Samuel Seoane Alberto Ocaña Atanasio Pandiella Juan Carlos Montero |
author_sort |
Ana Orive‐Ramos |
title |
Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications |
title_short |
Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications |
title_full |
Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications |
title_fullStr |
Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications |
title_full_unstemmed |
Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications |
title_sort |
regulation of the prometastatic neuregulin–mmp13 axis by src family kinases: therapeutic implications |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2017-12-01 |
description |
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. |
topic |
breast cancer dissemination dasatinib MMP13 neuregulin SRC |
url |
https://doi.org/10.1002/1878-0261.12145 |
work_keys_str_mv |
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