Abstract
BackgroundSubstance 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 DiscussionOverexpression 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.ConclusionOur 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.
Highlights
The cellular and non-cellular components of the tumor microenvironment shape tumor evolution[1]
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
Our results indicate that the transactivation of HER2 and EGFR by the pro-inflammatory cytokine/neuropeptide substance P (SP) in breast cancer (BC) cells is a c-Src and MMP-dependent process
Summary
The cellular and non-cellular components of the tumor microenvironment shape tumor evolution[1]. Among the components of the tumor microenvironment, the nervous system and the neuropeptides secreted by non-neuronal (i.e., by modulating immune cells) and neuronal cells appear to have a direct and indirect effects on tumor progression [2]. This is the case of neurokinin 1 receptor (NK-1R) (TACR1 gene) and its preferential ligand substance P (SP) (TAC1 gene), a pro-inflammatory cytokine and neuropeptide that belongs to the family of tachykinins [3, 4]. Substance P (SP) is a pleiotropic cytokine/neuropeptide that enhances breast cancer (BC) aggressiveness by transactivating tyrosine kinase receptors like EGFR and HER2. 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.
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