Cyr61 as mediator of Src signaling in triple negative breast cancer cells

María Pilar Sánchez-Bailón, Annarica Calcabrini, Víctor Mayoral-Varo, Agnese Molinari, Kay Uwe Wagner, Jesús Pérez Losada, Sergio Ciordia, Juan Pablo Albar, Jorge Martín-Pérez

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

SFKs are involved in tumorigenesis and metastasis. Here we analyzed c-Src contribution to initial steps of metastasis by tetracycline-dependent expression of a specific shRNA-c-Src, which suppressed c-Src mRNA and protein levels in metastatic MDA-MB-231 cells. c-Src suppression did not alter cell proliferation or survival, but it significantly reduced anchorage-independent growth. Concomitantly with diminished tyrosine-phosphorylation/activation of Fak, caveolin-1, paxillin and p130CAS, c-Src depletion also inhibited cellular migration, invasion and transendothelial migration. Quantitative proteomic analyses of the secretome showed that Cyr61 levels, which were detected in the exosomal fraction, were diminished upon shRNA-c-Src expression. In contrast, Cyr61 expression was unaltered inside cells. Cyr61 partially colocalized with cis-Golgi gp74 marker and with exosomal marker CD63, but c-Src depletion did not alter their cellular distribution. In SUM159PT cells, transient c-Src suppression also reduced secreted exosomal Cyr61 levels. Furthermore, conditional expression of a c-Src dominant negative mutant (SrcDN, c-Src-K295M/Y527F) in MDA-MB-231 and in SUM159PT diminished secreted Cyr61 as well. Cyr61 transient suppression in MDA-MB-231 inhibited invasion and transendothelial migration. Finally, in both MDA-MB-231 and SUM159PT, a neutralizing Cyr61 antibody restrained migration. Collectively, these results suggest that c-Src regulates secreted proteins, including the exosomal Cyr61, which are involved in modulating the metastatic potential of triple negative breast cancer cells.

Original languageEnglish (US)
Pages (from-to)13520-13538
Number of pages19
JournalOncotarget
Volume6
Issue number15
DOIs
StatePublished - 2015

Keywords

  • C-Src
  • Cyr61
  • Invasion
  • Migration
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology

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