Open AccessInterplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer
Author(s) -
Shanshan Deng,
Marco Ramos-Castañeda,
Walter V. Velasco,
Michael J. Clowers,
Berenice A. Gutierrez,
Oscar Noble,
Yanyan Dong,
Melody Zarghooni,
Lucero Alvarado,
Mauricio S. Caetano,
Shuanying Yang,
Edwin J. Ostrin,
Carmen Behrens,
Ignacio I. Wistuba,
Laura P. Stabile,
Humam Kadara,
Stephanie S. Watowich,
Seyed Javad Moghaddam
Publication year - 2020
Publication title -
carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.688
H-Index - 204
eISSN - 1460-2180
pISSN - 0143-3334
DOI - 10.1093/carcin/bgaa064
Subject(s) - carcinogenesis , cancer research , estrogen , immune system , tumor microenvironment , biology , lung cancer , adenocarcinoma , cancer , stat3 , tumor initiation , immunology , signal transduction , medicine , endocrinology , microbiology and biotechnology
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.