The exon 38-containing ARHGEF11 splice isoform is differentially expressed and is required for migration and growth in invasive breast cancer cells

Masahiko Itoh, Derek C. Radisky, Masaaki Hashiguchi, Hiroyuki Sugimoto

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Breast cancer invasion involves the loss of cell-cell junctions and acquisition of an invasive, migratory phenotype, and breast cancer cells of the basal intrinsic subtype are more invasive and metastatic than breast cancer cells of other subtypes. ARHGEF11 is a RhoGEF that was previously shown to bind to the tight junction protein ZO-1 at perijunctional actomyosin ring (PJAR), a network of cortically organized actin and myosin filaments associated with junctional complexes that regulates cellcell adhesion and polarization. We show here that ARHGEF11 shows splice isoform expression that differs according to the intrinsic subtype of breast cancer cells and that controls their invasive phenotype. Luminal subtype breast cancer cells express the isoform of ARHGEF11 lacking exon 38 (38-), which binds to ZO-1 at PJAR and is necessary for formation and maintenance of cell-cell junctions. Basal subtype breast cancer cells express the isoform of ARHGEF11 containing exon 38 (38+), which does not bind to ZO-1 and which drives cell migration and motility. Depletion of ARHGEF11 in basal subtype breast cancer cells is sufficient to alter cell morphology from a mesenchymal stellate form with extensive cell protrusions to a cobblestonelike epithelial form, and to suppress growth and survival both in vitro and in vivo. These findings show that the expression of the particular splice isoform of ARHGEF11 is critically linked to the malignant phenotype of breast cancer cells, identifying ARHGEF11 exon 38(+) as a biomarker and target for therapy of breast cancer.

Original languageEnglish (US)
Pages (from-to)92157-92170
Number of pages14
JournalOncotarget
Volume8
Issue number54
DOIs
StatePublished - 2017

Keywords

  • Alternative splicing
  • Breast cancer
  • Epithelial-mesenchymal transition
  • Invasion
  • RhoGEF

ASJC Scopus subject areas

  • Oncology

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