Itoh Masahiko, Radisky Derek C, Hashiguchi Masaaki, Sugimoto Hiroyuki
Department of Biochemistry, School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.
Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
Oncotarget. 2017 Sep 18;8(54):92157-92170. doi: 10.18632/oncotarget.20985. eCollection 2017 Nov 3.
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 and . 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.
乳腺癌侵袭涉及细胞间连接的丧失以及获得侵袭性、迁移性表型，并且基底内在亚型的乳腺癌细胞比其他亚型的乳腺癌细胞更具侵袭性和转移性。ARHGEF11是一种Rho鸟苷酸交换因子（RhoGEF），先前已证明它在连接周肌动球蛋白环（PJAR）处与紧密连接蛋白ZO-1结合，PJAR是一种与调节细胞间黏附和极化的连接复合体相关的皮质组织肌动蛋白和肌球蛋白丝网络。我们在此表明，ARHGEF11显示出根据乳腺癌细胞的内在亚型而不同的剪接异构体表达，并控制其侵袭性表型。管腔亚型乳腺癌细胞表达缺乏外显子38（38-）的ARHGEF11异构体，该异构体在PJAR处与ZO-1结合，是细胞间连接形成和维持所必需的。基底亚型乳腺癌细胞表达包含外显子38（38+）的ARHGEF11异构体，该异构体不与ZO-1结合，并驱动细胞迁移和运动。在基底亚型乳腺癌细胞中敲低ARHGEF11足以将细胞形态从具有广泛细胞突起的间充质星状形式改变为鹅卵石样上皮形式，并抑制体内和体外的生长与存活。这些发现表明，ARHGEF11特定剪接异构体的表达与乳腺癌细胞的恶性表型密切相关，将ARHGEF11外显子38（+）鉴定为乳腺癌治疗的生物标志物和靶点。
