PMID- 30265336 OWN - NLM STAT- MEDLINE DCOM- 20200203 LR - 20200203 IS - 1460-2105 (Electronic) IS - 0027-8874 (Linking) VI - 111 IP - 6 DP - 2019 Jun 1 TI - Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer. PG - 609-619 LID - 10.1093/jnci/djy151 [doi] AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer. CI - (c) The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Lee, Jeong-Yeon AU - Lee JY AD - Department of Medicine, College of Medicine. FAU - Joo, Hyeong-Seok AU - Joo HS AD - Department of Pathology, College of Medicine. FAU - Choi, Hee-Joo AU - Choi HJ AD - Department of Pathology, College of Medicine. FAU - Jin, Sora AU - Jin S AD - Department of Pathology, College of Medicine. FAU - Kim, Hyung-Yong AU - Kim HY AD - Department of Pathology, College of Medicine. FAU - Jeong, Ga-Young AU - Jeong GY AD - Department of Pathology, College of Medicine. FAU - An, Hee Woon AU - An HW AD - Department of Pathology, College of Medicine. FAU - Park, Mi Kyung AU - Park MK AD - Hanyang University, Seoul, Republic of Korea; National Cancer Center, Goyang, Republic of Korea. FAU - Lee, Seung Eun AU - Lee SE AD - Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea. FAU - Kim, Wan-Seop AU - Kim WS AD - Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea. FAU - Son, Taekwon AU - Son T AD - Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea. FAU - Min, Kyueng-Whan AU - Min KW AD - Department of Pathology, College of Medicine. FAU - Oh, Young-Ha AU - Oh YH AD - Department of Pathology, College of Medicine. FAU - Kong, Gu AU - Kong G AD - Department of Pathology, College of Medicine. LA - eng PT - Journal Article PL - United States TA - J Natl Cancer Inst JT - Journal of the National Cancer Institute JID - 7503089 RN - 0 (PCGF2 protein, human) RN - EC 2.3.2.27 (Polycomb Repressive Complex 1) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 3.4.24.81 (ADAM10 Protein) RN - EC 3.4.24.86 (ADAM17 Protein) RN - EC 3.4.24.86 (ADAM17 protein, human) RN - P188ANX8CK (Trastuzumab) SB - IM MH - ADAM10 Protein/antagonists & inhibitors/metabolism MH - ADAM17 Protein/antagonists & inhibitors/metabolism MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology MH - Breast Neoplasms/*drug therapy/*genetics/metabolism MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm MH - Female MH - Gene Amplification MH - Humans MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Polycomb Repressive Complex 1/*genetics MH - Receptor, ErbB-2/*antagonists & inhibitors/genetics/metabolism MH - Trastuzumab/administration & dosage MH - Xenograft Model Antitumor Assays EDAT- 2018/09/29 06:00 MHDA- 2020/02/06 06:00 CRDT- 2018/09/29 06:00 PHST- 2017/12/05 00:00 [received] PHST- 2018/06/23 00:00 [revised] PHST- 2018/08/03 00:00 [accepted] PHST- 2018/09/29 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2018/09/29 06:00 [entrez] AID - 5103386 [pii] AID - 10.1093/jnci/djy151 [doi] PST - ppublish SO - J Natl Cancer Inst. 2019 Jun 1;111(6):609-619. doi: 10.1093/jnci/djy151.