{"doi":"10.3390/ijms23158086","title":"miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer","abstract":"Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.","journal":"International Journal of Molecular Sciences","year":2022,"id":274215,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231086,"name":"Özge Saatci","orcid":"0000-0002-0124-044X","position":1,"is_corresponding":false},{"id":942757,"name":"Gourab Gupta","orcid":null,"position":2,"is_corresponding":false},{"id":555933,"name":"Yogin Patel","orcid":"0000-0002-1951-009X","position":3,"is_corresponding":false},{"id":577622,"name":"Manikanda Raja Keerthi Raja","orcid":"0009-0008-9587-8890","position":4,"is_corresponding":false},{"id":942289,"name":"Jie Li","orcid":"0000-0002-4734-1940","position":5,"is_corresponding":false},{"id":577623,"name":"Xinfeng Liu","orcid":"0000-0002-8182-9632","position":6,"is_corresponding":false},{"id":293249,"name":"Peisheng Xu","orcid":"0000-0002-4486-7058","position":7,"is_corresponding":false},{"id":577624,"name":"Hongjun Wang","orcid":"0000-0003-3455-8523","position":8,"is_corresponding":false},{"id":396954,"name":"Daping Fan","orcid":"0000-0002-4729-761X","position":9,"is_corresponding":false},{"id":231105,"name":"Özgür Şahin","orcid":"0000-0002-8033-7089","position":10,"is_corresponding":false},{"id":457324,"name":"Hexin Chen","orcid":"0000-0001-9300-0859","position":11,"is_corresponding":false},{"id":577621,"name":"Mithil Soni","orcid":"0000-0001-9387-0221","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T00:28:07.776043Z","pmid":"35897675","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}