Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer
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Siti Norasikin Mohd Nafi1, Daniele Generali4, Gabriela Kramer-Marek6, Merel Gijsen1, Carla Strina4, Mariarosa Cappelletti4, Daniele Andreis4, Syed Haider2 Ji-Liang Li2, Esther Bridges2, Jacek Capala3, Roxanis Ioannis5, 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 National Institutes of Health, Radiation Oncology Branch, Bethesda MD, US
4 U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Viale Concordia 1, Cremona, Italy
5 Department of Cellular Pathology, Oxford University Hospitals and Oxford Biomedical Research Centre, Oxford, UK
6 Institute of Cancer Research, Division of Radiotherapy and Imaging, 15 Cotswold Road, Belmont, Sutton, Surrey, UK
Anthony Kong , email:
Keywords: breast cancer, HER4, HER2, trastuzumab, resistance
Received: February 1, 2014 Accepted: April 16, 2014 Published: April 17, 2014
The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer.
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