Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer

Shanshan Deng, Marco Ramos-Castaneda, Walter V Velasco, Michael J Clowers, Berenice A Gutierrez, Oscar Noble, Yiping 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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1529-1542
Number of pages14
JournalCarcinogenesis
Volume41
Issue number11
DOIs
StatePublished - Nov 13 2020

Keywords

  • Adenocarcinoma of Lung/immunology
  • Animals
  • Cell Transformation, Neoplastic/immunology
  • Estrogens/metabolism
  • Female
  • Humans
  • Immunity/immunology
  • Immunomodulation
  • Lung Neoplasms/immunology
  • Male
  • Mice
  • Mutation
  • NF-kappa B/genetics
  • Proto-Oncogene Proteins p21(ras)/genetics
  • STAT3 Transcription Factor/genetics
  • Tumor Cells, Cultured

Fingerprint

Dive into the research topics of 'Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer'. Together they form a unique fingerprint.

Cite this