title: ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer.
abstract: Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.
authors: Human Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors: Katharina
authors: K
authors: Feldinger
authors: U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Cremona, Italy.
authors: Daniele
authors: D
authors: Generali
authors: National Institutes of Health, Radiation Oncology Branch, Bethesda MD, US. Institute of Cancer Research, Division of Radiotherapy and Imaging, Belmont, Sutton, Surrey, UK (New address).
authors: Gabriela
authors: G
authors: Kramer-Marek
authors: Human Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors: Merel
authors: M
authors: Gijsen
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Tai Po Road, Sha Tin, Hong Kong.
authors: T B
authors: TB
authors: Ng
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Tai Po Road, Sha Tin, Hong Kong.
authors: Jack Ho
authors: JH
authors: Wong
authors: U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Cremona, Italy.
authors: Carla
authors: C
authors: Strina
authors: U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Cremona, Italy.
authors: Mariarosa
authors: M
authors: Cappelletti
authors: U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Cremona, Italy.
authors: Daniele
authors: D
authors: Andreis
authors: Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors: Ji-Liang
authors: JL
authors: Li
authors: Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors: Esther
authors: E
authors: Bridges
authors: Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors: Helen
authors: H
authors: Turley
authors: Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors: Russell
authors: R
authors: Leek
authors: Department of Cellular Pathology, Oxford University Hospitals and Oxford Biomedical Research Centre, Oxford, UK.
authors: Ioannis
authors: I
authors: Roxanis
authors: National Institutes of Health, Radiation Oncology Branch, Bethesda MD, US.
authors: Jacek
authors: J
authors: Capala
authors: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
authors: Gillian
authors: G
authors: Murphy
authors: Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors: Adrian L
authors: AL
authors: Harris
authors: Human Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors: Anthony
authors: A
authors: Kong
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C491236:ADAM10 protein, human