title: Integrin α3β1-CD151 complex regulates dimerization of ErbB2 via RhoA.
abstract: Integrin α3β1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of α3β1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of α3β1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of α3β1-depleted cells was reproduced upon depletion of tetraspanin CD151 and mirrored that of the cells treated with Herceptin, an established ErbB2 antagonist. Breast cancer cells expressing the α3β1-CD151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with α3β1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in α3β1-CD151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both α3β1 and CD151. We also found that the level of active RhoA was increased in α3β1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of α3β1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of α3β1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the α3β1-CD151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression.
authors.affiliation: School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: V
authors.initials: V
authors.lastname: Novitskaya
authors.affiliation: Department of Pathology and Chemotherapy, Medical University of Łódź, Łódź, Poland.
authors.forename: H
authors.initials: H
authors.lastname: Romanska
authors.affiliation: Department of Pathology and Chemotherapy, Medical University of Łódź, Łódź, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Kordek
authors.affiliation: Department of Pathology and Chemotherapy, Medical University of Łódź, Łódź, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Potemski
authors.affiliation: Department of Pathology and Chemotherapy, Medical University of Łódź, Łódź, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Kusińska
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunts House, Guys Campus, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Parsons
authors.affiliation: School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: E
authors.initials: E
authors.lastname: Odintsova
authors.affiliation: School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: F
authors.initials: F
authors.lastname: Berditchevski
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D016764:Cell Polarity; D005260:Female; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D060185:Tetraspanin 24 / Q000378:metabolism*; D000068878:Trastuzumab; D020742:rhoA GTP-Binding Protein
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039201:Integrin alpha3beta1; D018719:Erb-b2 Receptor Tyrosine Kinases; D060185:Tetraspanin 24; D000068878:Trastuzumab; D020742:rhoA GTP-Binding Protein; C554715:CD151 protein, human; C066737:RHOA protein, human; C508053:ERBB2 protein, human