Integrin α6β4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells

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100 Scopus citations

Abstract

In advanced breast carcinomas, the α6β4 integrin is associated with a migratory and invasive phenotype. In our current study, we show that expression of the α6β4 integrin in MDA-MB-435 breast carcinoma cells leads to increased expression of the autocrine motility factor autotaxin, as determined by Affymetrix gene chip, real-time quantitative RT-PCR and immunoblot analyses. We further demonstrate that increased autotaxin secretion from integrin α6β4 expressing cells acts to enhance chemotaxis through its ability to convert lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and accounts for 80% of the motogenic activity of the conditioned medium. We determine that integrin α6β4-dependent overexpression of autotaxin in MDA-MB-435 cells is mediated by NFAT1, but not NFAT5, through the use of siRNAs that specifically target autotaxin, integrin β4, NFAT1 and NFAT5. Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin α6β4 expressing cells. In summary, we find that the α6β4 integrin potentiates autotaxin expression through the upregulation and activation of NFAT1. These observations highlight for the first time a mechanism by which NFAT transcription factors can facilitate an invasive and motile phenotype downstream of integrin α6β4 signaling.

Original languageEnglish
Pages (from-to)5125-5130
Number of pages6
JournalOncogene
Volume24
Issue number32
DOIs
StatePublished - Jul 28 2005

Bibliographical note

Funding Information:
We gratefully acknowledge Lance Liotta, Mary Stracke and Arthur Mercurio for reagents and cell lines. We also thank B Mark Evers, Sarita Sastry, Zobeida Cruz-Monserrate and Adriana Paulucci for helpful discussions and L Nicole Towers for technical assistance. This work was supported by the Center for Interdisciplinary Research in Women’s Health, the Gastrointestinal Research Interdisciplinary Program, John Sealy Foundation Memorial Endowment Fund and the Sealy Center for Cancer Cell Biology.

Keywords

  • Chemotaxis
  • Gene transcription
  • Integrin
  • Nuclear factor of activated T-cells (NFAT)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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