Somatostatin receptors 1 and 5 heterodimerize with epidermal growth factor receptor: Agonist-dependent modulation of the downstream MAPK signalling pathway in breast cancer cells |
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| Authors: | Heather L Watt Geetanjali D Kharmate Ujendra Kumar |
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| Institution: | 1. Faculty of Medicine, Department of Experimental Medicine, McGill University, Royal Victoria Hospital, Montreal, QC, Canada;2. Faculty of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, The University of British Columbia. Vancouver, BC, Canada;3. From the Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia,;4. the Department of Surgery, University of California, San Francisco, San Francisco, California 94143,;5. the Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts 02142, and;6. the Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California 94110;1. Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy;2. Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy;3. Pathophysiology and Transplantation, Università degli Studi di Milano, UO Medicina Interna 1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy;4. Biomeasure Incorporated/IPSEN, Milford, MA, USA;1. Centre Hospitalier Universitaire A Michallon, 38043 Grenoble, France;2. European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium;1. School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India;2. Division of Nuclear Medicine, Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India;3. Saha Institute of Nuclear Physics, Kolkata 700064, India;4. Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA;1. Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada;2. Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada;3. ITMO University, St. Petersburg 197101, Russia;4. Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA;5. Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada;6. Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada |
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| Abstract: | The role of somatostatin (SST) and epidermal growth factor (EGF) in breast cancer is undisputed; however, the molecular mechanisms underlying their antiproliferative or proliferative effects are not well understood. We initially confirmed that breast tumour tissues express all five somatostatin receptors (SSTR1-5) and four epidermal growth factor receptors (ErbB1-4). Subsequently, to gain insight into the function of SSTRs and ErbBs in oestrogen receptor (ER)-positive (MCF-7) or ERα-negative (MDA-MB-231) breast cancer cells, we defined SSTR1, SSTR5 and ErbB1 mRNA and protein expression in these two tumour cell lines. Consistent with previous studies showing SSTR1/SSTR5 heterodimerization and having seen cell-specific and ligand-selective alterations in receptor expression, we next elucidated whether SSTR1 and SSTR5 functionally interact with ErbB1 using pbFRET analysis. We subsequently determined the effects of SST and EGF either alone, or in combination, on selected downstream signalling molecules such as erk1/2, p38 and JNK. Here, we showed that both SST and EGF influenced erk1/2 phosphorylation and that SST modulated the effects of EGF in a cell-specific manner. We also demonstrated agonist-, time and cell-dependent regulation of p38 phosphorylation. We further investigated modulation of Grb2, SOS, Shc, SH-PTP1 and SH-PTP2. ErbB1 adaptor proteins known to play a role in MAPK activation, Shc, Grb2 and SOS, changed in an agonist- and cell-specific manner whereas, SH-PTP1 and SH-PTP2, adaptor proteins reported to interact with SSTRs, translocated from the cytosol to membrane in a cell-specific manner following SST and/or EGF treatment. Although several previous studies have shown crosstalk between RTKs and GPCRs, there are no reports describing SSTR (GPCR) modulation of ErbBs (RTK) in breast cancer. To the best of our knowledge, this is the first report describing crosstalk/interactions between SSTRs and ErbBs. |
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