Prognostic value of glutaminase 1 in breast cancer depends on H3K27me3 expression and menopausal status.

ABSTRACT

Glutaminase 1 (GLS) is a therapeutic target for breast cancer; although GLS inhibitors have been developed, only a few subjects responded well to the therapy. Considering that the expression of histone H3 lysine 27 trimethylation (H3K27me3) and menopausal status was closely linked to GLS, we examined the effects of H3K27me3 and menopausal status on GLS to breast cancer prognosis. Data for 962 women diagnosed with primary invasive breast cancer were analyzed. H3K27me3 and GLS expression in tumors were evaluated with tissue microarrays by immunohistochemistry. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival and progression-free survival were estimated using Cox regression models. Statistical interaction was assessed on multiplicative scale. There was a beneficial prognostic effect of GLS expression on overall survival for those with low H3K27me3 level (HR = 0.50, 95% CI 0.20-1.28) but an adverse prognostic effect for those with high H3K27me3 level (HR = 3.90, 95% CI 1.29-11.78) among premenopausal women, and the statistical interaction was significant (Pinteraction = 0.003). Similar pattern was further observed for progression-free survival (HR = 0.44, 95% CI 0.20-0.95 for low H3K27me3 level, HR = 1.35, 95% CI 0.74-2.48 for high H3K27me3 level, Pinteraction = 0.024). The statistical interaction did not occur among postmenopausal women. Our study showed that the prognostic effects of GLS on breast cancer correlated to the expression level of H3K27me3 and menopausal status, which would help optimize the medication strategies of GLS inhibitors.