CTMP, a predictive biomarker for trastuzumab resistance in HER2-enriched breast cancer patient

// Yu-Chia Chen 1, 2 , Hao-Yi Li 3 , Jui-Lin Liang 3, 4 , Luo-Ping Ger 5 , Hong-Tai Chang 2 , Michael Hsiao 6 , Marcus J. Calkins 3 , Hui-Chuan Cheng 3 , Jiin-Haur Chuang 1, 7 , Pei-Jung Lu 3 1 Graduate Institute of Clinical Medical Sciences, Medical College, Chang-Gung University, Tao-Yuan, Taiwan 2 Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 3 Institute of Clinical Medicine, Medical College, National Cheng Kung University, Tainan, Taiwan 4 Department of General Surgery, Chi-Mei Medical Center, Tainan, Taiwan 5 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 6 Genomics Research Center, Academia Sinica, Taipei, Taiwan 7 The Division of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan Correspondence to: Pei-Jung Lu, email: pjlu2190@mail.ncku.edu.tw Jiin-Haur Chuang, email: jhchuang@adm.cgmh.org.tw Keywords: CTMP, HER2, herceptin, trastuzumab, breast cancer Received: December 18, 2015      Accepted: May 28, 2016      Published: July 20, 2016 ABSTRACT Trastuzumab is regarded as the primary therapy for patients with HER2-enriched breast cancer, but the pathological complete response for advanced cases is less than 30%. The underlying mechanism of trastuzumab resistance remains unclear and there are currently no conclusive biomarkers for patient response to trastuzumab. Identifying predictive biomarkers for trastuzumab response may allow treatments to be individually tailored and optimized multi-target therapies may be developed. CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance. In this study, we examined samples from 369 patients to investigate the correlation between CTMP expression level and patient outcome. Elevated CTMP expression was correlated with adverse outcomes in HER2-enriched patients including overall and disease-free survival as well as trastuzumab resistance. Ectopic expression of varying levels of CTMP in SkBR3 cells dose-dependently attenuated trastuzumab-mediated growth inhibition through AKT activation. In addition, inhibition of AKT signaling by AKT inhibitor IV and Rapamycin reversed CTMP-mediated trastuzumab resistance. In clinical samples, the high expression of CTMP was showed in trastuzumab non-responders and positively correlated with AKT activity. Taken together, we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2-enriched breast cancer. High CTMP expression not only predicted poor prognosis, but may also predict resistance to trastuzumab in HER2-enriched patients. Therefore, CTMP expression may be considered as a prognostic biomarker in HER2-enriched breast cancer and high expression may indicate a utility for AKT-inhibition in these patients.