Interaction of H3K27me3 and Glutaminase 1 Expression on Breast Cancer Prognosis by Menopausal Status: a Cohort Study

Abstract Background: Glutaminase 1 (GLS) is a potential 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 trimethylation of histone H3 lysine 27 (H3K27me3) and menopausal status have been closely linked to the role of GLS, we tried to examine the modification effects of H3K27me3 and menopausal status on GLS to breast cancer prognosis, which would be helpful to identify the more suitable patients to the GLS inhibitors.Methods: Data for 963 women diagnosed with primary invasive breast cancer between 2008 and 2015 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 (OS) and progression-free survival (PFS) were estimated using univariable and multivariable Cox regression models. The interaction was assessed on multiplicative scale by stratification analysis.Results: After a median follow-up of 70.6 months (interquartile range: 45.6-103.9), we confirmed the association between H3K27me3 and both outcomes (HR =0.57, 95% CI: 0.37-0.86 for OS; HR =0.66, 95% CI: 0.48-0.91 for PFS) and found that the prognostic roles of GLS were not statistically significant in the overall patients. There was a beneficial prognostic effect of GLS expression on OS 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 interaction was significant (Pinteraction =0.003). Similar pattern was further observed for PFS (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 interaction didn’t occur among postmenopausal women.Conclusions: This study revealed the modification effects of H3K27me3 and menopausal status on GLS to breast cancer prognosis, which would help optimize the medication strategies related to GLS inhibitors.