Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer
DC Field | Value | Language |
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dc.contributor.author | Choi, Hee-Joo | - |
dc.contributor.author | Joo, Hyeong-Seok | - |
dc.contributor.author | Won, Hee-Young | - |
dc.contributor.author | Min, Kyueng-Whan | - |
dc.contributor.author | Kim, Hyung-Yong | - |
dc.contributor.author | Son, Taekwon | - |
dc.contributor.author | Oh, Young-Ha | - |
dc.contributor.author | Lee, Jeong-Yeon | - |
dc.contributor.author | Kong, Gu | - |
dc.date.accessioned | 2022-07-12T06:11:36Z | - |
dc.date.available | 2022-07-12T06:11:36Z | - |
dc.date.created | 2021-05-11 | - |
dc.date.issued | 2018-04 | - |
dc.identifier.issn | 0027-8874 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/150321 | - |
dc.description.abstract | Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by in vitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and in vivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. Results: RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance in vitro and in vivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm(3), vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm(3), P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1- HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001). Conclusions: RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | OXFORD UNIV PRESS INC | - |
dc.title | Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Min, Kyueng-Whan | - |
dc.contributor.affiliatedAuthor | Oh, Young-Ha | - |
dc.contributor.affiliatedAuthor | Lee, Jeong-Yeon | - |
dc.contributor.affiliatedAuthor | Kong, Gu | - |
dc.identifier.doi | 10.1093/jnci/djx207 | - |
dc.identifier.scopusid | 2-s2.0-85031692562 | - |
dc.identifier.wosid | 000430188100010 | - |
dc.identifier.bibliographicCitation | JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, v.110, no.4, pp.400 - 410 | - |
dc.relation.isPartOf | JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | - |
dc.citation.title | JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | - |
dc.citation.volume | 110 | - |
dc.citation.number | 4 | - |
dc.citation.startPage | 400 | - |
dc.citation.endPage | 410 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | Y | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.subject.keywordPlus | HISTONE DEMETHYLASE RBP2 | - |
dc.subject.keywordPlus | ESTROGEN-RECEPTOR BINDING | - |
dc.subject.keywordPlus | H3K4 DEMETHYLASE | - |
dc.subject.keywordPlus | TRANSCRIPTIONAL REPRESSION | - |
dc.subject.keywordPlus | ENDOCRINE RESISTANCE | - |
dc.subject.keywordPlus | GROWTH | - |
dc.subject.keywordPlus | PROTEINS | - |
dc.subject.keywordPlus | GENE | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | TUMORS | - |
dc.identifier.url | https://academic.oup.com/jnci/article/110/4/400/4443110 | - |
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