{"doi":"10.21873/anticanres.14810","title":"Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade","abstract":"BACKGROUND/AIM: Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+). MATERIALS AND METHODS: To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted. RESULTS: MAP3K6 was up-regulated in the T47DaromLR cells by 3.2-fold (p<0.01) which was associated with a decrease in relapse-free survival among breast cancer patients (p=0.0019). Members of the MAPK/p38 pathway (i.e., phospho-MKK6, phospho-p38, phospho-RSK1, phospho-RSK2, and p70S6K MAPK) were also increased in the T47DaromLR cells, while inhibiting p38 led to decreased proliferation and induction of apoptosis. CONCLUSION: Activation of the p38/MAPK pathway leads to ER+ AI-resistance.","journal":"Anticancer Research","year":2021,"id":192672,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"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":0.918,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":528174,"name":"Karen M. Gallegos","orcid":null,"position":1,"is_corresponding":false},{"id":510663,"name":"Melyssa R. Bratton","orcid":"0000-0001-9063-2025","position":2,"is_corresponding":false},{"id":760406,"name":"KiTani Parker Lemieux","orcid":null,"position":3,"is_corresponding":false},{"id":402649,"name":"Kun Zhang","orcid":"0000-0002-1915-788X","position":4,"is_corresponding":false},{"id":321424,"name":"Guangdi Wang","orcid":"0000-0002-3999-8213","position":5,"is_corresponding":false},{"id":527347,"name":"A. Michael Davidson","orcid":"0000-0002-7831-8532","position":6,"is_corresponding":false},{"id":527349,"name":"Syreeta L. Tilghman","orcid":"0000-0003-3215-1252","position":7,"is_corresponding":false},{"id":528172,"name":"Rashidra R. Walker","orcid":null,"position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:49:43.496702Z","pmid":"33517263","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":[]}