ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer
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Katharina Feldinger1, Daniele Generali3, Gabriela Kramer-Marek4,8, Merel Gijsen1, Tzi Bun Ng5, Jack Ho Wong5, Carla Strina3, Mariarosa Cappelletti3, Daniele Andreis3, Ji-Liang Li2, Esther Bridges2, Helen Turley2, Russell Leek2, Ioannis Roxanis6, Jacek Capala4, Gillian Murphy7, Adrian L. Harris2 and Anthony Kong1
1 Human Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
2 Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
3 U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Cremona, Italy
4 National Institutes of Health, Radiation Oncology Branch, Bethesda MD, US
5 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Tai Po Road, Sha Tin, Hong Kong
6 Department of Cellular Pathology, Oxford University Hospitals and Oxford Biomedical Research Centre, Oxford, UK
7 Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
8 Institute of Cancer Research, Division of Radiotherapy and Imaging, Belmont, Sutton, Surrey, UK (New address)
Anthony Kong, email:
Keywords: Trastuzumab, resistance, ADAM10, HER2, survival
Received: March 8, 2014 Accepted: May 7, 2014 Published: May 8, 2014
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.
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