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Background <p>Breast cancer (BC) remains the most commonly diagnosed malignancy among women worldwide, with metabolic dysregulation of glucose and hyperinsulinemia increasingly recognised as contributors to its development and progression. However, despite accumulating evidence linking metabolic imbalances to tumorigenesis, the precise therapeutic opportunities arising from targeting these metabolic pathways remain insufficiently defined.</p> Objective <p>To explore the potential of metformin and its derivatives, in combination with other anticancer agents, to suppress BC cell proliferation by targeting glucose metabolism.</p> Results <p>Preclinical and epidemiological evidence indicates that metformin may reduce BC incidence and improve survival, with particularly pronounced benefits observed in triple-negative and Human Epidermal Growth Factor Receptor 2(HER2) positive subtypes, especially when used in combination with chemotherapy or targeted therapies. The drug’s anticancer potential is mediated through both systemic and tumor-intrinsic mechanisms. Systemically, metformin enhances insulin sensitivity and suppresses hepatic glucose production, thereby lowering circulating insulin and IGF-1 levels and attenuating growth factor–driven proliferation. At the tumor level, it activates AMP-activated protein kinase, inhibits the mammalian target of rapamycin pathway, disrupts mitochondrial oxidative phosphorylation, and induces apoptosis through metabolic stress. In addition, novel biguanide derivatives have demonstrated superior antitumor efficacy by inducing cell-cycle arrest at the G0/G1 and G2/M phases and inhibiting cancer cell migration, underscoring the therapeutic promise of structural modifications. However, despite these encouraging findings, restuls from large clinical trials have been inconsistent, particularly in non-diabetic populations, and the extent to which metformin’s metabolic effects translate into direct oncologic benefit remains unclear. Importantly, elevated systemic insulin and IGF-1 remain key drivers of mitogenic and anti-apoptotic signaling in breast epithelial cells, reinforcing the rationale for targeting metabolic vulnerabilities in BC prevention and therapy.</p> Conclusion <p>Metformin and its derivatives exert dual anticancer effects by modulating systemic insulin signaling and targeting tumor-intrinsic pathways. Nevertheless, inconsistencies between preclinical efficacy and clinical outcomes highlight the need for biomarker-guided approaches and deeper investigation into tumour-specific metabolic contects. These complementary mechanisms highlight their potential in precision BC therapy, warranting biomarker-driven studies and optimized therapeutic combinations.</p>

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Metformin and its derivatives in breast cancer: from glycaemic control to tumor-intrinsic pathways

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Rohina Alim,
  • Hewa Marambage Kasuni Akalanka

摘要

Background

Breast cancer (BC) remains the most commonly diagnosed malignancy among women worldwide, with metabolic dysregulation of glucose and hyperinsulinemia increasingly recognised as contributors to its development and progression. However, despite accumulating evidence linking metabolic imbalances to tumorigenesis, the precise therapeutic opportunities arising from targeting these metabolic pathways remain insufficiently defined.

Objective

To explore the potential of metformin and its derivatives, in combination with other anticancer agents, to suppress BC cell proliferation by targeting glucose metabolism.

Results

Preclinical and epidemiological evidence indicates that metformin may reduce BC incidence and improve survival, with particularly pronounced benefits observed in triple-negative and Human Epidermal Growth Factor Receptor 2(HER2) positive subtypes, especially when used in combination with chemotherapy or targeted therapies. The drug’s anticancer potential is mediated through both systemic and tumor-intrinsic mechanisms. Systemically, metformin enhances insulin sensitivity and suppresses hepatic glucose production, thereby lowering circulating insulin and IGF-1 levels and attenuating growth factor–driven proliferation. At the tumor level, it activates AMP-activated protein kinase, inhibits the mammalian target of rapamycin pathway, disrupts mitochondrial oxidative phosphorylation, and induces apoptosis through metabolic stress. In addition, novel biguanide derivatives have demonstrated superior antitumor efficacy by inducing cell-cycle arrest at the G0/G1 and G2/M phases and inhibiting cancer cell migration, underscoring the therapeutic promise of structural modifications. However, despite these encouraging findings, restuls from large clinical trials have been inconsistent, particularly in non-diabetic populations, and the extent to which metformin’s metabolic effects translate into direct oncologic benefit remains unclear. Importantly, elevated systemic insulin and IGF-1 remain key drivers of mitogenic and anti-apoptotic signaling in breast epithelial cells, reinforcing the rationale for targeting metabolic vulnerabilities in BC prevention and therapy.

Conclusion

Metformin and its derivatives exert dual anticancer effects by modulating systemic insulin signaling and targeting tumor-intrinsic pathways. Nevertheless, inconsistencies between preclinical efficacy and clinical outcomes highlight the need for biomarker-guided approaches and deeper investigation into tumour-specific metabolic contects. These complementary mechanisms highlight their potential in precision BC therapy, warranting biomarker-driven studies and optimized therapeutic combinations.