{"doi":"10.3390/cancers13102340","title":"TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers","abstract":"JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.","journal":"Cancers","year":2021,"id":177310,"datarank":0.4566783656585135,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.0,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"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":721552,"name":"Noah R. Aguayo","orcid":null,"position":1,"is_corresponding":false},{"id":347637,"name":"Sara Abu Jalboush","orcid":"0009-0009-9913-4175","position":2,"is_corresponding":false},{"id":706577,"name":"Daniel Doheny","orcid":"0000-0002-1455-3090","position":3,"is_corresponding":false},{"id":721016,"name":"Sara G. Manore","orcid":"0000-0003-1962-5505","position":4,"is_corresponding":false},{"id":592807,"name":"Dongqin Zhu","orcid":null,"position":5,"is_corresponding":false},{"id":347636,"name":"Grace L. Wong","orcid":"0000-0001-5986-4952","position":6,"is_corresponding":false},{"id":706576,"name":"Austin Arrigo","orcid":"0000-0003-4857-4305","position":7,"is_corresponding":false},{"id":721553,"name":"Calvin J. Wagner","orcid":null,"position":8,"is_corresponding":false},{"id":721017,"name":"Yang Yu","orcid":"0000-0002-0549-8755","position":9,"is_corresponding":false},{"id":266597,"name":"Alexandra Thomas","orcid":"0000-0001-9022-2229","position":10,"is_corresponding":false},{"id":281346,"name":"Michael D. Chan","orcid":"0000-0002-5278-6709","position":11,"is_corresponding":false},{"id":281347,"name":"Jimmy Ruiz","orcid":"0000-0002-7242-3315","position":12,"is_corresponding":false},{"id":673492,"name":"Guangxu Jin","orcid":"0000-0001-9451-4886","position":13,"is_corresponding":false},{"id":255139,"name":"Roy E. Strowd","orcid":"0000-0001-6651-5267","position":14,"is_corresponding":false},{"id":331693,"name":"Peiqing Sun","orcid":"0000-0003-2255-6504","position":15,"is_corresponding":false},{"id":721018,"name":"Jiayuh Lin","orcid":"0000-0002-5618-8781","position":16,"is_corresponding":false},{"id":347638,"name":"Hui‐Wen Lo","orcid":"0000-0002-0681-7914","position":17,"is_corresponding":false},{"id":706575,"name":"Angelina T. Regua","orcid":"0000-0003-2595-8242","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:47:28.018172Z","pmid":"34066153","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":[]}