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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • Binbin Tan,
  • Yang Liu,
  • Qianqian Chen,
  • Weijie Yang,
  • Wenhan Yang,
  • Kaiping Gao,
  • Li Fu,
  • Tiantian Zhang,
  • Penglong Chen,
  • Yongyi Huang,
  • Yuting Wang,
  • Guoqiang Zhang,
  • Juan Xiong,
  • Rihong Zhai

摘要

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.