Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac.

Breast cancer (BC) is the most common tumor worldwide and it has been recognized that up to one third of BC patients have co-existing diabetes mellitus (DM) (BC-DM). Although many observational studies have indicated an association between DM and BC, the causal relationship of DM and BC prognosis remained uncertain and the molecular mechanisms underlying BC-DM are largely unclear. In this study, we used causal inference methods, including g-computation (GC), inverse probability of treatment weighting (IPTW), targeted maximum likelihood estimation (TMLE), and TMLE-super learner (TMLE-SL), to comprehensively analyze the association of DM with BC mortality in a cohort of 3386 BC patients. We found that the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for 5-year mortality in BC-DM patients were 1.926 (1.082, 2.943), 2.268 (1.063, 3.974), 1.917 (1.091, 2.953), and 2.113 (1.365, 3.270), respectively. Further transcriptomic and qPCR analyses identified that FIBCD1 was highly expressed in BC-DM tumor tissues and in BC cells under hyperglycemia conditions. Functionally, upregulation of FIBCD1 promoted proliferation, migration, and invasion capacities of BC cells in a glucose level-dependent manner. While knockdown of FIBCD1 suppressed BC tumor growth in diabetic mice. Integrated RNA-seq and Ribo-seq analysis revealed that MCM5 was a target of FIBCD1. Mechanistically, hyperglycemia-activated FIBCD1 promoted MCM5 expression to induce S-phase cell cycle arrest by upregulating histone H3K27ac levels in MCM5 promoter via the PDH-acetyl-CoA axis. Our findings provide new evidence that co-existing DM has a causal effect on overall mortality in BC-DM patients. Targeting FIBCD1 may be a promising therapy for BC-DM.