Research Papers:

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 and Hiroyuki Sugimoto

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Oncotarget. 2017; 8:92157-92170. https://doi.org/10.18632/oncotarget.20985

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Masahiko Itoh1, Derek C. Radisky2, Masaaki Hashiguchi3 and Hiroyuki Sugimoto1

1Department of Biochemistry, School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan

2Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA

3Department of Immunology, School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan

Correspondence to:

Masahiko Itoh, email: [email protected]

Keywords: breast cancer, epithelial-mesenchymal transition, invasion, alternative splicing, RhoGEF

Received: July 18, 2017    Accepted: August 21, 2017    Published: September 18, 2017


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 cell-cell 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 cobblestone-like 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.

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