NF-κB and STAT3 signaling uniquely stratify survival in female glioblastoma patients

The mechanisms underlying sex differences in glioblastoma (GBM) incidence, treatment response, and survival are not well understood. Increased activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling is associated with shorter survival in GBM. We looked at the expression of NF-κB- or STAT3-related genes in GBM for evidence of a sex skew in activity. Survival analysis of male and female GBM patients revealed that NF-κB- or STAT3-related gene expression was correlated with shorter survival only in female patients. We further explored mechanisms of this sex effect in an established murine model of sex differences in GBM. Concordant with human data, female murine GBM cells expressed stronger signatures of NF-κB and STAT3 genes and exhibited stronger responses to pathway stimulation and inhibition than their male counterparts. This study illustrates the advantage of sex-stratified data analysis in the development of sex-informed treatments for greater precision in cancer treatments.