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Título:	The transmodulation of HER2 and EGFR by Substance P in breast cancer cells requires c-Src and metalloproteinase activation.
Autor/a:	Garcia Recio, Susana; Pastor Arroyo, Eva M.; Marín Aguilera, Mercedes; Almendro Navarro, Vanessa; Gascón, Pere
Notas:	BACKGROUND: Substance P (SP) is a pleiotropic cytokine/neuropeptide that enhances breast cancer (BC) aggressiveness by transactivating tyrosine kinase receptors like EGFR and HER2. We previously showed that SP and its cognate receptor NK-1 (SP/NK1-R) signaling modulates the basal phosphorylation of HER2 and EGFR in BC, increasing aggressiveness and drug resistance. In order to elucidate the mechanisms responsible for NK-1R-mediated HER2 and EGFR transactivation, we investigated the involvement of c-Src (a ligand-independent mediator) and of metalloproteinases (ligand-dependent mediators) in HER2/EGFR activation. RESULTS AND DISCUSSION: Overexpression of NK-1R in MDA-MB-231 and its chemical inhibition in SK-BR-3, BT-474 and MDA-MB-468 BC cells significantly modulated c-Src activation, suggesting that this protein is a mediator of NK-1R signaling. In addition, the c-Src inhibitor 4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2. On the other hand, SP-dependent phosphorylation of HER2 and EGFR decreased substantially in the presence of the MMP inhibitor 1-10, phenanthroline monohydrate, and the dual inhibition of both c-Src and MMP almost abolished the activation of HER2 and EGFR. Moreover, the use of these inhibitors demonstrated that this Src and MMP-dependent signaling is important to the cell viability and migration capacity of HER2+ and EGFR+ cell lines. CONCLUSION: Our results indicate that the transactivation of HER2 and EGFR by the pro-inflammatory cytokine/neuropeptide SP in BC cells is a c-Src and MMP-dependent process.
Materia(s):	-Càncer de mama -Genètica molecular -Metal·loproteïnes -Breast cancer -Molecular genetics -Metalloproteins
Derechos:	cc-by (c) Garcia Recio, Susana et al., 2015 http://creativecommons.org/licenses/by/3.0/es
Tipo de documento:	Artículo Artículo - Versión publicada
Editor:	Public Library of Science (PLoS)
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