A bidirectional "αvβ3 integrin-ERK1/ERK2 MAPK" connection regulates the proliferation of breast cancer cells

Luciano Vellon, Javier A. Menendez, Ruth Lupu

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

In addition to their role in cell migration and adhesion, integrins elicit a series of transduction events that regulate cell-cycle progression and apoptosis in a process known as "outside-in" signaling. A second mode of integrin regulation known as "inside-out" signaling, in which the activation of major cell transduction cascades can influence the activation status of some integrins, has also been described. Here, we have assessed the role of the extracellular signal-regulated kinase (ERK1)/ERK2, mitogen-activated protein kinase (MAPK), and phospoinositide 3-kinase (PI-3′K) signaling pathways in the expression and function of αvβ3 integrin in breast cancer models. Pharmacological inhibition of MEK1 and MEK2 with U0126 drastically increased the levels of αvβ 3 in Heregulin (HRG)-overexpressing MDA-MB-231 cells (231/WT, 231/VEC) and derivatives transfected with the antisense orientation of the HRG-β2 full length cDNA (231/ASPOOL, 231/AS31). Interestingly, this was related to a significant decrease of viability and of the S- and G2/M subcompartment of the cell cycle in MDA MB 231 cells in response to U0126. Furthermore, specific inhibition of the PI-3′K pathway with LY294002 also induced an increase of αvβ3 levels but to a lesser extent. Moreover, pretreatment of MDA-MB-231 cells with U0126 antagonized the effects of small peptidomimetic αvβ3 antagonists. Remarkably, inhibition of the PI-3′K/AKT pathway did not exert the same effects, thus suggesting that the "outside-in" as well as the "inside-out" αvβ3-mediated signaling goes primarily through the ERK1/ERK2 MAPK pathway in MDA MB 231 breast cancer cells. Collectively, these results strongly suggest the existence of a bidirectional molecular connection αvβ3-ERK1/ ERK2 MAPK that would regulate breast cancer cells survival and proliferation.

Original languageEnglish (US)
Pages (from-to)795-804
Number of pages10
JournalMolecular Carcinogenesis
Volume45
Issue number10
DOIs
StatePublished - Oct 1 2006

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Keywords

  • Breast cancer
  • Integrins
  • MAPK
  • PI-3′K
  • αβ

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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