Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer
DC Field | Value | Language |
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dc.contributor.author | Lee, Jeong-Yeon | - |
dc.contributor.author | Joo, Hyeong-Seok | - |
dc.contributor.author | Choi, Hee-Joo | - |
dc.contributor.author | Jin, Sora | - |
dc.contributor.author | Kim, Hyung-Yong | - |
dc.contributor.author | Jeong, Ga-Young | - |
dc.contributor.author | An, Hee Woon | - |
dc.contributor.author | Park, Mi Kyung | - |
dc.contributor.author | Lee, Seung Eun | - |
dc.contributor.author | Kim, Wan-Seop | - |
dc.contributor.author | Son, Taekwon | - |
dc.contributor.author | Min, Kyueng-Whan | - |
dc.contributor.author | Oh, Young-Ha | - |
dc.contributor.author | Kong, Gu | - |
dc.date.accessioned | 2022-12-20T10:41:50Z | - |
dc.date.available | 2022-12-20T10:41:50Z | - |
dc.date.created | 2022-12-09 | - |
dc.date.issued | 2019-06 | - |
dc.identifier.issn | 0027-8874 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/173274 | - |
dc.description.abstract | 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] mm(3), vs trastuzumab + GW280264 30mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm(3), 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. | - |
dc.publisher | Oxford University Press | - |
dc.title | Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, Jeong-Yeon | - |
dc.identifier.doi | 10.1093/jnci/djy151 | - |
dc.identifier.scopusid | 2-s2.0-85068576620 | - |
dc.identifier.wosid | 000474267400011 | - |
dc.identifier.bibliographicCitation | Journal of the National Cancer Institute, v.111, no.6, pp.609 - 619 | - |
dc.relation.isPartOf | Journal of the National Cancer Institute | - |
dc.citation.title | Journal of the National Cancer Institute | - |
dc.citation.volume | 111 | - |
dc.citation.number | 6 | - |
dc.citation.startPage | 609 | - |
dc.citation.endPage | 619 | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.subject.keywordPlus | GROWTH-FACTOR RECEPTOR | - |
dc.subject.keywordPlus | TUMOR-SUPPRESSOR | - |
dc.subject.keywordPlus | H2A UBIQUITYLATION | - |
dc.subject.keywordPlus | DOWN-REGULATION | - |
dc.subject.keywordPlus | HER2 AMPLICON | - |
dc.subject.keywordPlus | STEM-CELLS | - |
dc.subject.keywordPlus | TRASTUZUMAB | - |
dc.subject.keywordPlus | RESISTANCE | - |
dc.subject.keywordPlus | EXPRESSION | - |
dc.subject.keywordPlus | SURVIVAL | - |
dc.identifier.url | https://academic.oup.com/jnci/article/111/6/609/5103386?login=true | - |
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