{"doi":"10.1093/carcin/bgaa064","title":"Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer","abstract":"K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.","journal":"Carcinogenesis","year":2020,"id":71606,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":379749,"name":"Marco Ramos-Castañeda","orcid":null,"position":1,"is_corresponding":false},{"id":378392,"name":"Walter V. Velasco","orcid":"0000-0001-9101-5758","position":2,"is_corresponding":false},{"id":378393,"name":"Michael J. Clowers","orcid":"0000-0002-5259-3464","position":3,"is_corresponding":false},{"id":378394,"name":"Berenice A. Gutierrez","orcid":"0000-0002-2756-1970","position":4,"is_corresponding":false},{"id":378395,"name":"Oscar Noble","orcid":"0000-0002-9842-8712","position":5,"is_corresponding":false},{"id":378396,"name":"Yiping Dong","orcid":"0000-0002-4601-370X","position":6,"is_corresponding":false},{"id":378397,"name":"Melody Zarghooni","orcid":"0000-0002-3765-3086","position":7,"is_corresponding":false},{"id":379750,"name":"Lucero Alvarado","orcid":null,"position":8,"is_corresponding":false},{"id":248068,"name":"Mauricio S. Caetano","orcid":null,"position":9,"is_corresponding":false},{"id":378398,"name":"Shuanying Yang","orcid":"0000-0002-9676-9302","position":10,"is_corresponding":false},{"id":239539,"name":"Edwin J. Ostrin","orcid":"0000-0002-4538-6539","position":11,"is_corresponding":false},{"id":69926,"name":"Carmen Behrens","orcid":"0000-0003-1905-8061","position":12,"is_corresponding":false},{"id":226199,"name":"Ignacio I. Wistuba","orcid":"0000-0003-3365-6340","position":13,"is_corresponding":false},{"id":378399,"name":"Laura P. Stabile","orcid":"0000-0002-1822-2707","position":14,"is_corresponding":false},{"id":268276,"name":"Humam Kadara","orcid":"0000-0003-2976-9115","position":15,"is_corresponding":false},{"id":277293,"name":"Stephanie S. Watowich","orcid":"0000-0003-1969-659X","position":16,"is_corresponding":false},{"id":378400,"name":"Seyed Javad Moghaddam","orcid":"0000-0002-5350-307X","position":17,"is_corresponding":false},{"id":378391,"name":"Shanshan Deng","orcid":"0000-0003-4646-5885","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-18T21:44:25.469842Z","pmid":"32603404","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":[]}