{"doi":"10.1530/erc-23-0148","title":"MicroRNA regulation of the serine synthesis pathway in endocrine-resistant breast cancer cells","abstract":"Despite the successful combination of therapies improving survival of estrogen receptor α (ER+) breast cancer patients with metastatic disease, mechanisms for acquired endocrine resistance remain to be fully elucidated. The RNA binding protein HNRNPA2B1 (A2B1), a reader of N(6)-methyladenosine (m6A) in transcribed RNA, is upregulated in endocrine-resistant, ER+ LCC9 and LY2 cells compared to parental MCF-7 endocrine-sensitive luminal A breast cancer cells. The miRNA-seq transcriptome of MCF-7 cells overexpressing A2B1 identified the serine metabolic processes pathway. Increased expression of two key enzymes in the serine synthesis pathway (SSP), phosphoserine aminotransferase 1 (PSAT1) and phosphoglycerate dehydrogenase (PHGDH), correlates with poor outcomes in ER+ breast patients who received tamoxifen (TAM). We reported that PSAT1 and PHGDH were higher in LCC9 and LY2 cells compared to MCF-7 cells and their knockdown enhanced TAM sensitivity in these-resistant cells. Here we demonstrate that stable, modest overexpression of A2B1 in MCF-7 cells increased PSAT1 and PHGDH and endocrine resistance. We identified four miRNAs downregulated in MCF-7-A2B1 cells that directly target the PSAT1 3'UTR (miR-145-5p and miR-424-5p), and the PHGDH 3'UTR (miR-34b-5p and miR-876-5p) in dual luciferase assays. Lower expression of miR-145-5p and miR-424-5p in LCC9 and ZR-75-1-4-OHT cells correlated with increased PSAT1 and lower expression of miR-34b-5p and miR-876-5p in LCC9 and ZR-75-1-4-OHT cells correlated with increased PHGDH. Transient transfection of these miRNAs restored endocrine-therapy sensitivity in LCC9 and ZR-75-1-4-OHT cells. Overall, our data suggest a role for decreased A2B1-regulated miRNAs in endocrine resistance and upregulation of the SSP to promote tumor progression in ER+ breast cancer.","journal":"Endocrine Related Cancer","year":2023,"id":358690,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":647974,"name":"Kellianne M. Piell","orcid":"0000-0002-4132-7304","position":1,"is_corresponding":false},{"id":648921,"name":"Ali E. Wilt","orcid":null,"position":2,"is_corresponding":false},{"id":1109466,"name":"Alexa D Howser","orcid":null,"position":3,"is_corresponding":false},{"id":1109467,"name":"Laura Winkler","orcid":null,"position":4,"is_corresponding":false},{"id":1109468,"name":"Mattie R Whitworth","orcid":null,"position":5,"is_corresponding":false},{"id":1109469,"name":"B Valdés","orcid":null,"position":6,"is_corresponding":false},{"id":70045,"name":"Norman L. Lehman","orcid":"0000-0001-8394-2607","position":7,"is_corresponding":false},{"id":374602,"name":"Brian F. Clem","orcid":"0000-0002-9082-8914","position":8,"is_corresponding":false},{"id":399371,"name":"Carolyn M. Klinge","orcid":"0000-0002-3358-4378","position":9,"is_corresponding":false},{"id":399369,"name":"Belinda J. Petri","orcid":"0000-0002-9248-9311","position":0,"is_corresponding":true}],"reference_count":166,"raw_metadata":null,"created_at":"2026-07-19T01:13:48.379546Z","pmid":"37650685","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":[]}