1. Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer
- Author
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Jeong-Yeon Lee, Taekwon Son, Hyeong Seok Joo, Hee Woon An, Sora Jin, Kyueng-Whan Min, Young Ha Oh, Hee Joo Choi, Gu Kong, Hyung-Yong Kim, Wan Seop Kim, Ga Young Jeong, Seung Eun Lee, and Mi Kyung Park
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-2 ,Breast Neoplasms ,Mice, SCID ,ADAM17 Protein ,ADAM10 Protein ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,Trastuzumab ,Cell Line, Tumor ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Polycomb Repressive Complex 1 ,business.industry ,Gene Amplification ,medicine.disease ,Xenograft Model Antitumor Assays ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Anti her2 ,business ,medicine.drug - Abstract
Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer.The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases). MEL-18 amplification was validated by fluorescence in situ hybridization (FISH) analysis. The MEL-18 effect on trastuzumab response was confirmed by in vitro cell viability assays and an in vivo xenograft experiment (n = 7 per group). Gene expression microarray and receptor tyrosine kinase array were performed to identify the trastuzumab resistance mechanism by MEL-18 loss. All statistical tests were two-sided.MEL-18 was exclusively amplified in approximately 30-50% of HER2+ breast tumors and was associated with a favorable clinical outcome (disease-free survival: P = .02 in HER2+ cases, METABRIC; P = .04 in patients receiving trastuzumab). In MEL-18-amplified HER2+ breast cancer, MEL-18 depletion induced trastuzumab resistance by increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization. MEL-18 epigenetically silenced ADAM10/17 expression in cooperation with polycomb-repressive complex (PRC) 1 and PRC2. Combination treatment with an ADAM10/17 inhibitor and trastuzumab could overcome MEL-18 loss-mediated trastuzumab resistance in vivo (BT474/shMEL-18 xenograft: trastuzumab, mean [SD] tumor volume = 406.1 [50.1] mm3, vs trastuzumab + GW280264 30 mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm3, P.001). Consistently, trastuzumab-treated patients harboring concomitant MEL-18 amplification and low ADAM17 expression showed prolonged relapse-free survival (P = .02 in our cohort, n = 213).MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer.
- Published
- 2018