The Interplay Between Breast Cancer and Diabetes Mellitus: Shared Mechanisms, Risk Factors, and Integrated Management Strategies

1. Introduction

Breast cancer and diabetes mellitus (DM) are two prevalent chronic diseases, each contributing significantly to global morbidity and mortality. Breast cancer is the most common malignancy in women, accounting for over 2.3 million new cases annually (Sung et al., 2021). Despite advancements in screening and treatment, disparities in outcomes persist, especially in low- and middle-income countries (Fidler-Benaoudia et al., 2020). Similarly, type 2 diabetes (T2D) is a growing global epidemic, affecting over 400 million people, with projections exceeding 600 million cases by 2040 (International Diabetes Federation, 2019). The coexistence of these conditions presents challenges, as diabetes increases the risk of breast cancer and worsens clinical outcomes (Boyle et al., 2012; Onah et al., 2024).

The association between diabetes and breast cancer is multifaceted, driven by overlapping risk factors and shared molecular mechanisms. Diabetic women face a 20–27% higher risk of developing breast cancer, with the risk particularly elevated in postmenopausal women (Boyle et al., 2012). Diabetes is also linked to poorer breast cancer prognosis, with higher recurrence and mortality rates (Barone et al., 2008; Ogunlakin et al. 2024). Obesity, sedentary lifestyles, and aging contribute to both diseases. Obesity promotes insulin resistance, chronic inflammation, and increased estrogen levels, driving tumorigenesis (Vona-Davis and Rose, 2007; Omiyale et al. 2024a, Omiyale et al. 2024b). Sedentary behavior and aging exacerbate these risks through systemic inflammation and metabolic dysfunction (Shoelson et al., 2006).

At the molecular level, hyperinsulinemia, chronic inflammation, and oxidative stress are key mechanisms linking diabetes to breast cancer. Insulin resistance leads to compensatory hyperinsulinemia, which activates insulin and IGF-1 signaling pathways, promoting cell proliferation and angiogenesis (Pollak, 2008). Chronic inflammation in diabetes further supports tumor growth by creating a pro-tumorigenic microenvironment and activating pro-survival pathways like NF-κB and STAT3 (Shoelson et al., 2006). Hyperglycemia-induced oxidative stress contributes to DNA damage, genomic instability, and cancer progression (Nishikawa et al., 2000).

Diabetes also induces epigenetic changes, including altered DNA methylation and histone modifications, which dysregulate tumor suppressor genes and oncogenes. These changes, along with metabolic reprogramming, provide cancer cells with the resources needed for rapid proliferation (Esteller, 2007; Vander Heiden et al., 2009). These shared mechanisms highlight the complex interplay between the two diseases.

The coexistence of diabetes and breast cancer complicates clinical management. Diabetes reduces the efficacy of cancer therapies, such as chemotherapy and endocrine therapy, while cancer treatments can disrupt glycemic control, requiring close monitoring (Jiralerspong et al., 2009). Integrated care approaches that address both conditions are essential to improving outcomes. Lifestyle modifications, including dietary changes and physical activity, reduce the risk of both diseases. Pharmacological strategies, such as metformin, show promise in improving glycemic control and exerting anti-tumor effects by inhibiting mTOR signaling and reducing hyperinsulinemia (Pollak, 2012). Other antidiabetic drugs, like GLP-1 receptor agonists and SGLT2 inhibitors, are under investigation for their potential cancer-preventive roles (Madsen et al., 2016; Scafoglio et al., 2015).

This review examines the relationship between breast cancer and diabetes, focusing on shared risk factors, molecular pathways, and clinical implications. By exploring the mechanisms linking these conditions, this review aims to provide insights into integrated prevention and management strategies to improve patient outcomes.

2. Breast Cancer Pathogenesis

2.1 Molecular Subtypes of Breast Cancer

Breast cancer is not a single disease but comprises distinct molecular subtypes that influence prognosis and therapeutic strategies. Based on gene expression profiling, breast cancer is classified into four major subtypes: Luminal A, Luminal B, HER2-enriched, and Triple-Negative Breast Cancer (TNBC) (Perou et al., 2000; Sorlie et al., 2001).

Luminal A: This subtype is characterized by ER and PR positivity, low HER2 expression, and low Ki-67 levels, reflecting a lower proliferation index. Luminal A tumors are associated with a favorable prognosis, with hormone therapy, particularly tamoxifen or aromatase inhibitors, forming the cornerstone of treatment (Howell et al., 2005).

Luminal B: Similar to Luminal A, Luminal B tumors express ER and PR but exhibit higher proliferation rates and a poorer prognosis. They often show partial HER2 positivity, necessitating combined endocrine and targeted therapies such as trastuzumab (Prat et al., 2015).

HER2-enriched: HER2-overexpressing tumors are aggressive but highly responsive to targeted HER2 inhibition, such as trastuzumab and pertuzumab. These tumors lack ER and PR expression and exhibit increased proliferation and metastatic potential (Hudis, 2007).

Triple-Negative Breast Cancer (TNBC): Lacking ER, PR, and HER2 expression, TNBC constitutes 15–20% of breast cancers and is associated with poor prognosis due to its aggressive nature and lack of targeted therapies. Chemotherapy remains the primary treatment option, although immune checkpoint inhibitors are emerging as potential therapies (Lehmann et al., 2011).

Molecular subtype classification has revolutionized breast cancer management by enabling precision medicine and individualized treatment strategies.

2.2 Genetic and Epigenetic Alterations

The development and progression of breast cancer are driven by a myriad of genetic and epigenetic changes that alter cellular processes such as proliferation, apoptosis, and DNA repair.

Genetic Alterations

BRCA1 and BRCA2 Mutations: Mutations in BRCA1 and BRCA2 genes are among the most well-established genetic drivers of breast cancer, particularly in hereditary cases. These genes encode proteins essential for homologous recombination-mediated DNA repair. Loss of their function leads to genomic instability, predisposing cells to malignant transformation (Roy et al., 2012).

TP53 Mutations: As a critical tumor suppressor, TP53 regulates apoptosis, cell cycle arrest, and DNA repair. TP53 mutations occur in over 20% of breast cancers, with higher prevalence in TNBC, where they contribute to unchecked proliferation and genomic instability (Kastenhuber and Lowe, 2017).

PIK3CA Mutations: Activating mutations in PIK3CA, which encodes the catalytic subunit of PI3K, are common in ER-positive breast cancers and drive oncogenic signaling by activating the AKT/mTOR pathway. These alterations represent therapeutic targets, with PI3K inhibitors like alpelisib demonstrating clinical efficacy (Miller et al., 2021).

Epigenetic Modifications

Epigenetic dysregulation complements genetic alterations in breast cancer pathogenesis:

DNA Methylation: Aberrant promoter hypermethylation leads to silencing of tumor suppressor genes, such as CDH1, responsible for maintaining cell-cell adhesion (Esteller, 2007). Loss of E-cadherin promotes EMT and metastasis.

Histone Modifications: Changes in histone acetylation and methylation alter chromatin accessibility, impacting gene expression. For example, overexpression of histone deacetylases (HDACs) in breast cancer correlates with poor prognosis and resistance to therapy (Park et al., 2011).

Non-Coding RNAs: MicroRNAs and long non-coding RNAs (lncRNAs) regulate gene expression post-transcriptionally. Dysregulation of miR-21, a well-known oncomiR, promotes breast cancer progression by targeting tumor suppressors such as PTEN (Iorio et al., 2005).

2.3 Tumor Microenvironment

The tumor microenvironment (TME) plays a pivotal role in breast cancer progression, influencing immune evasion, angiogenesis, and metastasis.

Cellular Components of the TME

Cancer-Associated Fibroblasts (CAFs): CAFs secrete growth factors, cytokines, and ECM components that support tumor growth and invasion. Transforming growth factor-beta (TGF-β) released by CAFs induces EMT, enhancing the metastatic potential of breast cancer cells (Kalluri, 2016).

Immune Cells: Immune cells within the TME exhibit dichotomous roles:

• Tumor-Associated Macrophages (TAMs): Predominantly M2-polarized TAMs suppress anti-tumor immunity and promote angiogenesis and tissue remodeling (Mantovani et al., 2008).
• Cytotoxic T Cells: While cytotoxic T cells target cancer cells, their function is often suppressed by regulatory T cells (Tregs) and immune checkpoint molecules like PD-1 and CTLA-4 (Chen and Mellman, 2017).

ECM Remodeling and Angiogenesis

Matrix metalloproteinases (MMPs) degrade ECM components, facilitating cancer cell invasion and metastasis. Concurrently, hypoxia within tumors drives angiogenesis through the HIF-1α pathway, enabling tumors to access nutrients and oxygen necessary for growth (Semenza, 2012).

2.4 Hormonal Regulation

Hormonal signaling is a cornerstone of breast cancer pathogenesis, particularly in ER-positive subtypes.

Estrogen Receptor Signaling: Estrogen promotes breast cancer proliferation through its receptor (ER), a nuclear transcription factor. Binding of estrogen to ER activates transcription of genes involved in cell cycle progression, such as CCND1 (cyclin D1), driving mitosis (Hall et al., 2000). ER-positive tumors are highly dependent on this pathway, making them susceptible to endocrine therapies such as selective ER modulators (SERMs) and aromatase inhibitors (Johnston and Dowsett, 2003).

Progesterone and Prolactin: Progesterone, acting through its receptor (PR), modulates the proliferative effects of estrogen. In some contexts, it synergizes with estrogen to promote tumor growth, highlighting the complexity of hormonal crosstalk (Jacobsen et al., 2003). Similarly, prolactin signaling, mediated through the JAK2/STAT5 pathway, has been implicated in promoting breast cancer progression (Goffin et al., 2002).

2.5 Emerging Molecular Mechanisms

With advances in genomics and transcriptomics, novel mechanisms contributing to breast cancer pathogenesis have emerged:

• Cancer Stem Cells (CSCs): A subpopulation of self-renewing cells within tumors, CSCs are implicated in therapy resistance and metastasis. Their regulation by pathways such as Wnt, Notch, and Hedgehog underscores their importance as therapeutic targets (Al-Hajj et al., 2003).
• Metabolic Reprogramming: Breast cancer cells undergo metabolic adaptations, such as increased glycolysis and lipid biosynthesis, to meet the demands of rapid proliferation. Targeting metabolic pathways offers a promising therapeutic avenue (Vander Heiden et al., 2009).

Conclusion of Section 2

The pathogenesis of breast cancer is a multifaceted process driven by genetic, epigenetic, hormonal, and microenvironmental factors. Advances in molecular biology have not only deepened our understanding of these mechanisms but also paved the way for targeted therapies tailored to the distinct subtypes of breast cancer. Ongoing research into the TME, CSCs, and metabolic reprogramming holds promise for improving outcomes in this complex disease.

3. Diabetes Mellitus: Overview and Pathogenesis

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Its prevalence is rapidly increasing worldwide, driven by factors such as aging populations, obesity, and sedentary lifestyles. While the clinical manifestations and complications of DM are well-documented, its intricate pathogenesis continues to be an area of active research, particularly concerning its role in promoting oncogenesis and cancer progression.

3.1 Types of Diabetes Mellitus

Diabetes mellitus encompasses multiple types, each with distinct etiologies and pathophysiological mechanisms:

Type 1 Diabetes Mellitus (T1D): An autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. T1D accounts for 5–10% of all diabetes cases and typically presents in childhood or adolescence. The autoimmune attack involves the activation of autoreactive T cells against beta cell antigens, leading to severe insulin deficiency (Knip and Siljander, 2008).

Type 2 Diabetes Mellitus (T2D): The most common form, T2D results from a combination of insulin resistance and inadequate compensatory insulin secretion. It is closely associated with obesity and metabolic syndrome and constitutes over 90% of global diabetes cases (DeFronzo et al., 2015).

Gestational Diabetes Mellitus (GDM): Defined as glucose intolerance with onset or first recognition during pregnancy, GDM increases the risk of both maternal and fetal complications and predisposes women to T2D later in life (Buchanan et al., 2012).

Monogenic Diabetes: Rare forms of diabetes caused by single-gene mutations affecting beta cell function or insulin action. Examples include maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM) (Fajans et al., 2001).

3.2 Pathophysiology of Type 2 Diabetes Mellitus

The pathogenesis of T2D is multifactorial, involving complex interactions between genetic, environmental, and behavioral factors. Central to T2D is the failure of insulin-sensitive tissues—such as skeletal muscle, adipose tissue, and liver—to respond adequately to circulating insulin, a condition termed insulin resistance.

3.2.1 Insulin Resistance

Insulin resistance is the hallmark of T2D and is characterized by impaired glucose uptake in peripheral tissues and excessive hepatic glucose production. Molecular mechanisms underlying insulin resistance include:

• Post-Receptor Signaling Defects: Dysregulation of the insulin receptor substrate (IRS) proteins and downstream signaling pathways, particularly the PI3K/AKT pathway, leads to impaired glucose uptake in muscle and adipose tissues (Taniguchi et al., 2006).
• Inflammation-Induced Insulin Resistance: Adipose tissue inflammation, driven by macrophage infiltration and secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-6), disrupts insulin signaling. This occurs through serine phosphorylation of IRS proteins, which inhibits their ability to propagate insulin receptor signals (Shoelson et al., 2006).
• Lipid Accumulation and Lipotoxicity: Increased free fatty acid levels and ectopic lipid deposition in insulin-sensitive tissues induce lipotoxicity, further impairing insulin action. Ceramides and diacylglycerols, lipid intermediates, play a key role in this process (Samuel and Shulman, 2012).

3.2.2 Beta Cell Dysfunction

In response to insulin resistance, pancreatic beta cells initially compensate by increasing insulin secretion. Over time, beta cells become dysfunctional and fail to meet the body’s insulin demands. Key contributors to beta cell dysfunction include:

• Glucotoxicity: Chronic hyperglycemia exerts toxic effects on beta cells by increasing oxidative stress, promoting endoplasmic reticulum (ER) stress, and inducing beta cell apoptosis (Poitout and Robertson, 2008).
• Lipotoxicity: Prolonged exposure to elevated free fatty acids impairs insulin secretion and promotes beta cell death.
• Genetic Susceptibility: Variants in genes such as TCF7L2, KCNJ11, and SLC30A8 have been implicated in beta cell dysfunction and T2D risk (Prasad and Groop, 2015).

3.3 Chronic Hyperglycemia and Its Systemic Effects

Chronic hyperglycemia in DM has far-reaching consequences, affecting multiple organ systems. These effects are mediated through several mechanisms:

3.3.1 Advanced Glycation End Products (AGEs)

Persistent hyperglycemia leads to the non-enzymatic glycation of proteins and lipids, forming AGEs. AGEs bind to their receptor (RAGE) on various cell types, triggering oxidative stress and inflammation. In endothelial cells, AGEs contribute to vascular damage, a key feature of diabetic complications (Brownlee, 2001).

3.3.2 Oxidative Stress

Hyperglycemia-induced oxidative stress arises from excessive production of reactive oxygen species (ROS) by mitochondria. Elevated ROS levels damage cellular components, including DNA, proteins, and lipids, promoting inflammation and cell death (Nishikawa et al., 2000).

3.3.3 Polyol Pathway Activation

In hyperglycemic states, excess glucose is metabolized through the polyol pathway, resulting in the accumulation of sorbitol and fructose. This process depletes intracellular NADPH, reducing antioxidant defenses and exacerbating oxidative stress (Adegbesan et al. 2021; Obrosova, 2009).

3.3.4 Protein Kinase C (PKC) Activation

Hyperglycemia activates PKC isoforms, which mediate various pathological effects, including vascular permeability, angiogenesis, and inflammation. PKC activation has been implicated in both microvascular and macrovascular complications of DM (Geraldes and King, 2010).

3.4 Chronic Inflammation in Diabetes Mellitus

A growing body of evidence links low-grade chronic inflammation to the development and progression of DM. Adipose tissue plays a central role in this inflammatory process:

• Adipokines and Cytokines: Obesity-induced dysregulation of adipokines, such as leptin and adiponectin, disrupts insulin sensitivity. Pro-inflammatory cytokines secreted by adipose tissue, including TNF-α and IL-6, further impair insulin action (Xu et al., 2003).
• Macrophage Polarization: In lean individuals, adipose tissue contains predominantly M2 macrophages with anti-inflammatory functions. In obesity, M1 macrophages dominate, secreting pro-inflammatory mediators that promote insulin resistance (Lumeng et al., 2007).
• Inflammasome Activation: The NLRP3 inflammasome, a multiprotein complex, is activated in obesity and diabetes, leading to the production of IL-1β, a key mediator of beta cell dysfunction and systemic inflammation (Stienstra et al., 2011).

3.5 Complications of Diabetes Mellitus

The long-term complications of DM can be broadly categorized into microvascular and macrovascular complications:

• Microvascular Complications: Include diabetic retinopathy, nephropathy, and neuropathy, arising from damage to small blood vessels due to hyperglycemia-induced oxidative stress and inflammation.
• Macrovascular Complications: Include atherosclerosis, coronary artery disease, and peripheral vascular disease. Chronic hyperglycemia, dyslipidemia, and inflammation accelerate atherogenesis in DM patients (Beckman et al., 2002).
• Cancer Risk: DM, particularly T2D, is associated with an increased risk of several cancers, including breast cancer. Shared mechanisms, such as hyperinsulinemia, chronic inflammation, and oxidative stress, contribute to this association (Giovannucci et al., 2010).

Conclusion of Section 3

The pathogenesis of diabetes mellitus is multifaceted, involving complex interactions between genetic predisposition, environmental factors, and systemic metabolic dysregulation. Chronic hyperglycemia, insulin resistance, and inflammation form the cornerstone of this disorder and create a pro-tumorigenic environment that links DM to breast cancer. Understanding these mechanisms provides a foundation for developing targeted interventions to mitigate the risk and progression of both diseases.

4. Intersection of Breast Cancer and Diabetes Mellitus

The interplay between breast cancer and diabetes mellitus (DM), particularly type 2 diabetes (T2D), has gained significant attention due to their increasing global prevalence and overlapping risk factors. Epidemiological studies suggest that women with T2D have a 20–27% increased risk of developing breast cancer compared to non-diabetic individuals (Boyle et al., 2012). This association is multifaceted, involving shared risk factors, hormonal and metabolic dysregulation, chronic inflammation, and genetic predispositions. This section explores the mechanisms linking these two diseases and their implications for disease prevention and management.

4.1 Shared Risk Factors

Several risk factors contribute to the overlap between breast cancer and DM. These include obesity, sedentary lifestyle, age, and genetic susceptibility. The interplay of these risk factors creates an environment conducive to the development of both diseases.

4.1.1 Obesity

Obesity is a major modifiable risk factor for both breast cancer and T2D. Excess adipose tissue is a source of chronic inflammation, oxidative stress, and hormonal imbalances that promote tumorigenesis and insulin resistance.

• Adipokines: Obesity alters the balance of adipokines, which are cytokines secreted by adipose tissue. Leptin, a pro-inflammatory adipokine, is overproduced in obesity and promotes cancer cell proliferation by activating the JAK/STAT, PI3K/AKT, and MAPK pathways (Vona-Davis and Rose, 2007). In contrast, adiponectin, an anti-inflammatory adipokine, is reduced in obesity and T2D, contributing to insulin resistance and tumor progression (Renehan et al., 2015).
• Insulin Resistance: Obesity-induced insulin resistance increases circulating insulin and insulin-like growth factor-1 (IGF-1), which have mitogenic and anti-apoptotic effects on breast epithelial cells (Pollak, 2008).

4.1.2 Sedentary Lifestyle and Diet

A sedentary lifestyle, combined with high-calorie diets rich in refined carbohydrates and fats, contributes to both obesity and metabolic syndrome. Lack of physical activity reduces insulin sensitivity and increases circulating estrogen levels, exacerbating breast cancer risk in postmenopausal women (Petersen et al., 2003).

4.1.3 Age

The incidence of both breast cancer and T2D increases with age, reflecting cumulative exposure to risk factors such as hormonal fluctuations, obesity, and chronic inflammation. Postmenopausal women with T2D are at higher risk due to decreased estrogen levels and metabolic alterations associated with aging (Panjari and Davis, 2007).

4.1.4 Genetic Susceptibility

Genetic variants predisposing individuals to T2D may also influence breast cancer risk. For example, single nucleotide polymorphisms (SNPs) in genes involved in insulin signaling and cell proliferation, such as TCF7L2 and IGF1R, have been implicated in both conditions (Prasad and Groop, 2015).

4.2 Hormonal Dysregulation

The hormonal changes associated with T2D and obesity play a significant role in linking these conditions to breast cancer. Two key hormonal systems—insulin/IGF-1 signaling and estrogen pathways—are particularly relevant.

4.2.1 Insulin and IGF-1 Signaling

Hyperinsulinemia and elevated IGF-1 levels, common in T2D, create a pro-tumorigenic environment. Insulin and IGF-1 exert their effects through the insulin receptor (IR) and IGF-1 receptor (IGF-1R), respectively, activating downstream pathways such as PI3K/AKT and RAS/RAF/MEK/ERK. These pathways promote cell proliferation, survival, and angiogenesis, key hallmarks of cancer (Pollak, 2008).

Crosstalk with Estrogen Receptors: Insulin and IGF-1 signaling pathways interact with estrogen receptor (ER) signaling in breast cancer cells, enhancing ER activity and driving tumor growth (Kleinberg et al., 2009).

4.2.2 Estrogen and Androgens

Postmenopausal women with T2D have higher circulating levels of bioavailable estrogen due to increased aromatase activity in adipose tissue. This estrogen excess stimulates the growth of ER-positive breast cancers. Additionally, androgen levels, which are elevated in some cases of T2D, may indirectly contribute to tumor progression by serving as precursors for estrogen synthesis (Panjari and Davis, 2007).

4.3 Hyperglycemia and Oxidative Stress

Chronic hyperglycemia in DM exacerbates oxidative stress, which is a critical factor in cancer initiation and progression. Hyperglycemia drives the production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS), which directly damage DNA, proteins, and lipids.

• AGE-RAGE Axis: AGEs interact with their receptor (RAGE) to activate pro-inflammatory and pro-oncogenic pathways, including NF-κB signaling. This contributes to cancer cell survival, angiogenesis, and metastasis (Brownlee, 2001).
• ROS and DNA Damage: Hyperglycemia-induced ROS production causes DNA strand breaks, mutations, and genomic instability, providing a substrate for tumorigenesis. ROS also activate hypoxia-inducible factor-1α (HIF-1α), enhancing angiogenesis and tumor cell metabolism (Nishikawa et al., 2000).

4.4 Chronic Inflammation

Low-grade chronic inflammation is a hallmark of both T2D and cancer. The inflammatory milieu in T2D promotes breast cancer development by fostering a supportive microenvironment for tumor initiation and progression.

• Cytokines and Chemokines: Pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β are elevated in T2D and obesity. These cytokines activate NF-κB and STAT3 signaling pathways in breast epithelial cells, promoting proliferation, invasion, and immune evasion (Shoelson et al., 2006).
• Macrophage Infiltration: Adipose tissue in obesity exhibits increased infiltration of M1 macrophages, which secrete pro-inflammatory mediators that impair insulin sensitivity and promote tumorigenesis (Lumeng et al., 2007).
• Adipose-Derived Stromal Cells (ADSCs): ADSCs recruited to breast tumors in obese individuals enhance cancer cell migration, invasion, and angiogenesis through paracrine signaling (Zhao et al., 2015).

4.5 Epigenetic and Metabolic Links

Emerging evidence highlights the role of epigenetic changes and metabolic reprogramming in bridging DM and breast cancer. Epigenetic alterations such as DNA methylation and histone modifications induced by hyperglycemia may dysregulate tumor suppressor genes and oncogenes (Esteller, 2007). Additionally, metabolic adaptations common to both conditions, such as increased glycolysis (Warburg effect), lipid biosynthesis, and mitochondrial dysfunction, create a favorable environment for cancer progression (Vander Heiden et al., 2009; Edema et al. 2023).

Conclusion of Section 4

The intersection of breast cancer and diabetes mellitus is driven by a convergence of shared risk factors, hormonal dysregulation, chronic inflammation, and metabolic alterations. These interconnected pathways not only increase the risk of breast cancer in diabetic individuals but also influence tumor behavior and treatment outcomes. Understanding these mechanisms is essential for developing integrated preventive and therapeutic strategies targeting both diseases.

5. Molecular Pathways Linking Diabetes Mellitus and Breast Cancer

The relationship between diabetes mellitus (DM), particularly type 2 diabetes (T2D), and breast cancer is mediated through complex molecular pathways. Hyperinsulinemia, chronic hyperglycemia, oxidative stress, and chronic inflammation in diabetes converge on signaling pathways that promote breast cancer initiation, progression, and metastasis. This section explores the key molecular pathways linking DM to breast cancer, focusing on their roles in tumorigenesis, angiogenesis, immune evasion, and treatment resistance.

5.1 Insulin and IGF-1 Signaling Axis

One of the primary mechanisms linking DM to breast cancer involves hyperinsulinemia and the insulin-like growth factor-1 (IGF-1) signaling pathway. Insulin and IGF-1 are critical regulators of cell growth and metabolism, and their dysregulation in DM creates a pro-tumorigenic environment.

5.1.1 Hyperinsulinemia and Insulin Receptor (IR) Activation

In T2D, insulin resistance in peripheral tissues leads to compensatory hyperinsulinemia. Excess circulating insulin binds to insulin receptors (IR) on breast epithelial cells, particularly IR-A, a fetal isoform with higher mitogenic potential than metabolic activity (Pollak, 2008). This activates downstream signaling pathways, including:

• PI3K/AKT Pathway: Activation of phosphatidylinositol-3 kinase (PI3K) and protein kinase B (AKT) promotes cell survival, proliferation, and metabolic reprogramming. AKT also inhibits apoptosis by phosphorylating pro-apoptotic proteins such as BAD and caspase-9 (Miller et al., 2021).
• RAS/RAF/MEK/ERK Pathway: Insulin signaling activates the mitogen-activated protein kinase (MAPK) cascade, promoting cell cycle progression and tumor growth.

5.1.2 IGF-1 and IGF-1 Receptor (IGF-1R) Activation

Insulin resistance suppresses IGF-binding proteins (IGFBPs), increasing bioavailable IGF-1. IGF-1 binds to IGF-1 receptors (IGF-1R) on breast cancer cells, amplifying mitogenic and anti-apoptotic signals through pathways overlapping with insulin signaling (Pollak, 2008). Cross-talk between IGF-1R and estrogen receptor (ER) further enhances tumor progression in ER-positive breast cancers (Kleinberg et al., 2009).

5.2 AMPK and mTOR Signaling

The AMP-activated protein kinase (AMPK) pathway, a master regulator of energy homeostasis, is often dysregulated in DM. AMPK is activated under low-energy conditions, inhibiting anabolic processes such as lipid and protein synthesis while promoting catabolic pathways.

5.2.1 AMPK Suppression in DM

In T2D, AMPK activity is suppressed by chronic hyperglycemia, hyperlipidemia, and nutrient excess. This suppression removes the inhibitory effects of AMPK on mechanistic target of rapamycin (mTOR), a key driver of tumor growth and metabolism (Hardie et al., 2012). Dysregulated mTOR signaling promotes:

• Protein Synthesis: mTOR stimulates ribosomal protein S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), enhancing translation of oncogenic proteins.
• Lipid Biosynthesis: mTOR activity supports de novo lipid synthesis, providing membranes and energy for rapidly proliferating tumor cells (Vander Heiden et al., 2009).

5.2.2 Metformin and AMPK Activation

Metformin, a first-line anti-diabetic drug, exerts anti-cancer effects by activating AMPK. It inhibits mTOR signaling and decreases circulating insulin levels, reducing breast cancer growth, particularly in hyperinsulinemic conditions (Pollak, 2012).

5.3 Chronic Inflammation and NF-κB Pathway

Low-grade chronic inflammation is a hallmark of both DM and breast cancer. The nuclear factor-kappa B (NF-κB) pathway plays a central role in mediating inflammatory responses and is frequently activated in both conditions.

5.3.1 Inflammatory Cytokines and Adipokines

Adipose tissue inflammation in DM leads to the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and dysregulation of adipokines (e.g., increased leptin and decreased adiponectin). These factors activate NF-κB, promoting:

• Proliferation and Survival: NF-κB induces the expression of anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) and pro-proliferative genes (e.g., cyclin D1).
• Angiogenesis: NF-κB stimulates vascular endothelial growth factor (VEGF) production, enhancing angiogenesis and supporting tumor growth (Shoelson et al., 2006).

5.3.2 Inflammasome Activation

In obesity and DM, activation of the NLRP3 inflammasome in macrophages and adipocytes results in the production of IL-1β, a cytokine implicated in beta cell dysfunction and tumor promotion (Stienstra et al., 2011). IL-1β enhances cancer cell invasion and metastasis through epithelial-to-mesenchymal transition (EMT).

5.4 Hyperglycemia and Oxidative Stress

Chronic hyperglycemia in DM generates oxidative stress, a key driver of DNA damage, mutation accumulation, and tumorigenesis.

5.4.1 Reactive Oxygen Species (ROS)

Hyperglycemia increases mitochondrial ROS production, leading to:

• DNA Damage: ROS induces double-strand breaks and base modifications, promoting genomic instability in breast epithelial cells (Nishikawa et al., 2000).
• Oncogenic Pathway Activation: ROS activates oncogenic signaling pathways, including HIF-1α, NF-κB, and MAPK, driving tumor proliferation and angiogenesis.

5.4.2 Advanced Glycation End-Products (AGEs)

Hyperglycemia leads to the formation of AGEs, which bind to their receptor (RAGE) on cancer and stromal cells. AGE-RAGE interactions enhance ROS production and activate pro-inflammatory pathways, creating a tumor-supportive microenvironment (Brownlee, 2001).

5.5 Epigenetic Modifications

Hyperglycemia and insulin resistance in DM induce epigenetic changes that dysregulate gene expression in breast cancer cells.

5.5.1 DNA Methylation

In DM, hyperglycemia alters DNA methylation patterns, silencing tumor suppressor genes (e.g., CDKN2A) and activating oncogenes (e.g., MYC). These epigenetic changes promote cancer cell survival and proliferation (Esteller, 2007).

5.5.2 Histone Modifications

Histone acetylation and methylation are dysregulated in DM, leading to chromatin remodeling that facilitates the expression of pro-oncogenic genes. For instance, increased acetylation of histones in cancer cells enhances transcription of genes involved in cell cycle progression and angiogenesis (Park et al., 2011).

5.5.3 MicroRNAs (miRNAs)

Dysregulation of miRNAs in DM contributes to breast cancer pathogenesis. For example, downregulation of miR-126, an angiogenesis inhibitor, has been observed in both diabetic and breast cancer tissues, promoting VEGF expression and tumor vascularization (Iorio et al., 2005).

5.6 Immune Evasion and Tumor Microenvironment

Hyperinsulinemia, chronic inflammation, and oxidative stress in DM reshape the tumor microenvironment (TME), facilitating immune evasion.

5.6.1 Tumor-Associated Macrophages (TAMs)

Diabetes-associated inflammation promotes the polarization of macrophages into the M2 phenotype within the TME. M2 macrophages suppress cytotoxic T-cell responses, secrete VEGF, and support tumor growth and metastasis (Mantovani et al., 2008).

5.6.2 Regulatory T Cells (Tregs)

Hyperglycemia and chronic inflammation enhance the recruitment of Tregs to the TME, suppressing anti-tumor immune responses. Tregs inhibit effector T-cell activity through cytokines such as TGF-β and IL-10, enabling immune evasion (Chen and Mellman, 2017).

Conclusion of Section 5

The molecular pathways linking DM and breast cancer involve a complex network of insulin and IGF-1 signaling, chronic inflammation, oxidative stress, and epigenetic modifications. These mechanisms not only enhance tumor initiation and progression but also contribute to therapy resistance, underscoring the need for integrative treatment approaches targeting these shared pathways. Understanding these molecular links provides a foundation for developing preventive and therapeutic strategies to improve outcomes in patients with both diseases.

6. Clinical Implications

The interplay between diabetes mellitus (DM) and breast cancer has significant clinical implications, influencing risk assessment, treatment strategies, and patient outcomes. Women with diabetes face a higher risk of developing breast cancer and often experience worse prognoses due to the combined effects of metabolic dysregulation and cancer pathophysiology. This section explores the impact of DM on breast cancer prognosis, the influence of hyperglycemia and insulin resistance on treatment efficacy, and the emerging role of antidiabetic medications in modifying cancer outcomes.

6.1 Impact of Diabetes on Breast Cancer Prognosis

Numerous studies have highlighted the adverse effects of DM on breast cancer outcomes, including increased mortality, recurrence, and treatment complications.

6.1.1 Increased Breast Cancer Mortality in Diabetic Patients

Diabetic women with breast cancer have a 40–50% higher risk of mortality compared to non-diabetic patients (Barone et al., 2008). This disparity can be attributed to several factors:

• Tumor Aggressiveness: Chronic hyperglycemia and insulin resistance promote aggressive tumor phenotypes by enhancing proliferation, angiogenesis, and metastasis (Zhao et al., 2015).
• Delayed Diagnosis: Diabetic patients may receive delayed cancer diagnoses due to overlapping symptoms, reduced access to care, or misattribution of symptoms to diabetes-related complications (Peairs et al., 2011).

6.1.2 Increased Risk of Recurrence

DM is associated with a higher risk of breast cancer recurrence, particularly in patients with poor glycemic control. Hyperglycemia and chronic inflammation provide a supportive microenvironment for dormant tumor cells to reactivate and proliferate (Boyle et al., 2012).

6.1.3 Comorbidities and Treatment Tolerability

Comorbid conditions, such as cardiovascular disease, neuropathy, and nephropathy, are common in diabetic patients and may limit the use of certain breast cancer treatments, such as anthracyclines or trastuzumab, due to their cardiotoxicity (Hershman et al., 2011).

6.2 Influence on Breast Cancer Treatment

The metabolic changes associated with DM can directly and indirectly affect the efficacy and safety of breast cancer therapies.

6.2.1 Chemotherapy

Chemotherapy, a cornerstone of breast cancer treatment, may be less effective in diabetic patients due to:

• Hyperglycemia: High glucose levels in the tumor microenvironment reduce the effectiveness of certain chemotherapeutic agents, such as doxorubicin and paclitaxel, by altering drug uptake and resistance mechanisms (Jiralerspong et al., 2009).
• Insulin Resistance: Insulin promotes tumor cell survival, counteracting the apoptotic effects of chemotherapy (Goodwin et al., 2012).

6.2.2 Endocrine Therapy

Diabetes, particularly T2D, can affect the response to endocrine therapy in hormone receptor-positive breast cancers. Insulin resistance enhances cross-talk between insulin/IGF-1 signaling and estrogen receptor pathways, potentially reducing the efficacy of tamoxifen and aromatase inhibitors (Pollak, 2008).

6.2.3 Targeted Therapy

Targeted therapies, such as HER2 inhibitors (trastuzumab, pertuzumab) and CDK4/6 inhibitors (palbociclib), are effective in specific breast cancer subtypes. However, these treatments may exacerbate metabolic disturbances, such as hyperglycemia and insulin resistance, complicating management in diabetic patients (Pritchard et al., 2016).

6.2.4 Immunotherapy

Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 therapies, are emerging as promising treatments for breast cancer. However, the inflammatory milieu of diabetes may alter the immune response, reducing the efficacy of these therapies. Additionally, immune-related adverse events, such as autoimmune diabetes, may occur more frequently in patients with pre-existing diabetes (Leonardi et al., 2021).

6.3 Role of Antidiabetic Medications in Breast Cancer

Antidiabetic medications have gained attention for their potential to modify breast cancer risk and progression. Several drugs, including metformin, thiazolidinediones, and SGLT2 inhibitors, exhibit anti-cancer properties through direct and indirect mechanisms.

6.3.1 Metformin

Metformin, a widely used biguanide, has demonstrated significant anti-tumor effects in both preclinical and clinical studies:

• Mechanisms of Action: Metformin activates AMPK, inhibiting mTOR signaling and reducing tumor cell proliferation. It also lowers circulating insulin and IGF-1 levels, reducing pro-tumorigenic signaling (Pollak, 2012).
• Clinical Evidence: Retrospective studies have shown that metformin use is associated with improved survival and reduced recurrence rates in diabetic breast cancer patients (Niraula et al., 2012). Ongoing clinical trials are evaluating its efficacy in non-diabetic cancer patients.

6.3.2 Thiazolidinediones (TZDs)

TZDs, such as pioglitazone, improve insulin sensitivity by activating peroxisome proliferator-activated receptor-gamma (PPAR-γ). Preclinical studies suggest that PPAR-γ activation inhibits breast cancer cell growth by inducing cell cycle arrest and apoptosis (Chaffer et al., 2006). However, concerns about TZD-associated cardiovascular risks have limited their widespread use.

6.3.3 SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin, reduce hyperglycemia by promoting renal glucose excretion. Emerging evidence suggests that SGLT2 inhibitors may exhibit anti-tumor effects by altering cancer cell metabolism and reducing oxidative stress (Scafoglio et al., 2015).

6.3.4 GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, improve glycemic control and exhibit anti-inflammatory effects. Preliminary studies indicate that GLP-1 agonists may inhibit breast cancer cell proliferation, although more robust clinical evidence is needed (Madsen et al., 2016).

6.4 Integrated Management of Breast Cancer and Diabetes

Given the bidirectional relationship between DM and breast cancer, an integrated approach is essential to optimize outcomes for patients with both conditions.

6.4.1 Multidisciplinary Care

Collaboration between oncologists, endocrinologists, and primary care providers is critical to manage the unique challenges posed by comorbid DM and breast cancer. Regular monitoring of glycemic control, lipid profiles, and cardiovascular health should be incorporated into cancer treatment plans (Hershey et al., 2017).

6.4.2 Personalized Treatment Strategies

Treatment strategies should be tailored based on the patient’s glycemic status, comorbidities, and cancer subtype (Ogunjobi et al. 2025). For instance:

• Metformin may be prioritized in diabetic patients with ER-positive breast cancer due to its dual benefits in glycemic control and tumor suppression.
• Cardiotoxic therapies should be avoided or closely monitored in patients with diabetic cardiomyopathy.

6.4.3 Lifestyle Interventions

Lifestyle modifications, including diet, exercise, and weight management, are critical for improving glycemic control and reducing cancer risk. Physical activity enhances insulin sensitivity and reduces systemic inflammation, benefiting both DM and cancer outcomes (Rock et al., 2020).

Conclusion of Section 6

Diabetes mellitus significantly impacts breast cancer prognosis and treatment efficacy, complicating the management of affected patients. However, the emerging role of antidiabetic medications, particularly metformin, offers promising avenues for improving outcomes. Integrated, multidisciplinary approaches are essential to address the complex interplay between these diseases, ensuring personalized and effective care for patients with comorbid DM and breast cancer.

7. Prevention and Management

The bidirectional relationship between diabetes mellitus (DM) and breast cancer highlights the need for integrated preventive and therapeutic strategies. Both diseases share modifiable risk factors such as obesity, physical inactivity, and poor dietary habits, which can be targeted to reduce their incidence and improve outcomes. This section explores lifestyle interventions, pharmacological strategies, and emerging therapeutic approaches for the prevention and management of DM and breast cancer.

7.1 Lifestyle Interventions

Lifestyle modifications are central to reducing the risk of both DM and breast cancer. These interventions include dietary changes, physical activity, and weight management, all of which address shared risk factors.

7.1.1 Dietary Modifications

Diet plays a pivotal role in preventing and managing DM and reducing breast cancer risk. Evidence-based dietary interventions include:

• Low-Glycemic Index Diets: Foods with a low glycemic index reduce postprandial glucose spikes and improve insulin sensitivity, mitigating DM progression. Such diets may also lower breast cancer risk by reducing insulin and IGF-1 levels (Salmerón et al., 1997).
• Mediterranean Diet: Rich in fruits, vegetables, whole grains, nuts, and olive oil, the Mediterranean diet has been associated with a reduced risk of breast cancer and improved glycemic control in diabetic patients (Schwingshackl et al., 2015).
• Caloric Restriction: Weight loss achieved through caloric restriction improves insulin sensitivity and reduces circulating estrogen levels, potentially lowering breast cancer risk (Patterson et al., 2011).

7.1.2 Physical Activity

Regular physical activity reduces the risk of DM and breast cancer through several mechanisms:

• Enhancing insulin sensitivity and glucose uptake in muscle cells.
• Reducing systemic inflammation and adiposity.
• Lowering circulating levels of estrogen and IGF-1 (Rock et al., 2020). Guidelines recommend at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous activity per week for significant health benefits (WHO, 2020).

7.1.3 Weight Management

Obesity is a major shared risk factor for DM and breast cancer. Weight loss interventions, particularly in overweight or obese individuals, are associated with improved glycemic control and reduced breast cancer risk (Renehan et al., 2015).

7.2 Pharmacological Approaches

Pharmacological interventions play a critical role in managing DM and may also influence breast cancer risk and progression. The choice of antidiabetic medication can have significant implications for breast cancer outcomes.

7.2.1 Metformin

Metformin is the most extensively studied antidiabetic drug for its potential anti-cancer effects:

• Mechanisms in Cancer Prevention: Metformin reduces hyperinsulinemia, activates AMPK, and inhibits mTOR signaling, which collectively suppress tumor growth (Pollak, 2012).
• Clinical Evidence: Observational studies suggest that metformin use is associated with a 30% reduction in breast cancer risk and improved survival in diabetic patients with breast cancer (Niraula et al., 2012). Clinical trials are ongoing to evaluate its use in non-diabetic cancer patients.

7.2.2 GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, improve glycemic control and have shown promise in preclinical cancer models:

• Mechanisms: GLP-1 agonists may inhibit cancer cell proliferation and angiogenesis through metabolic and anti-inflammatory effects (Madsen et al., 2016).
• Clinical Evidence: Studies are ongoing to determine their role in breast cancer prevention.

7.2.3 SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin, lower blood glucose by promoting renal glucose excretion. Emerging evidence suggests they may also exhibit anti-cancer properties:

• Mechanisms: SGLT2 inhibitors alter cancer cell metabolism and reduce oxidative stress, potentially limiting tumor growth (Scafoglio et al., 2015).

7.2.4 Anti-Inflammatory Agents

Anti-inflammatory drugs targeting key mediators such as IL-6, TNF-α, and NF-κB signaling pathways are being explored for their dual benefits in DM and cancer. Aspirin and other NSAIDs have shown potential in reducing the risk of cancer, including breast cancer, in observational studies (Rothwell et al., 2011).

7.3 Emerging Therapeutic Strategies

Advances in molecular biology and personalized medicine are opening new avenues for integrated prevention and treatment of DM and breast cancer.

7.3.1 Targeting the Insulin/IGF-1 Axis

Therapies aimed at inhibiting insulin and IGF-1 signaling pathways hold promise for reducing tumor growth in diabetic patients. Drugs such as IGF-1 receptor inhibitors and insulin-sensitizing agents are under investigation (Pollak, 2008).

7.3.2 Epigenetic Therapy:

Epigenetic modifications, such as DNA methylation and histone acetylation, play a key role in both DM and cancer. Epigenetic therapies, including histone deacetylase (HDAC) inhibitors, are being explored as potential treatments for breast cancer, particularly in patients with diabetes-induced epigenetic changes (Esteller, 2007).

7.3.3 Immunotherapy

Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1 therapies, have revolutionized cancer treatment. Strategies to optimize their use in diabetic patients include addressing the pro-inflammatory and immunosuppressive environment associated with DM (Leonardi et al., 2021).

7.4 Integrated Care Approaches

Given the intricate relationship between DM and breast cancer, a multidisciplinary approach is essential for effective management.

7.4.1 Multidisciplinary Teams

Collaboration between oncologists, endocrinologists, primary care physicians, and dietitians ensures comprehensive care. Multidisciplinary teams can:

• Monitor glycemic control during cancer therapy.
• Manage comorbidities such as cardiovascular disease and nephropathy.
• Provide tailored nutritional and lifestyle guidance.

7.4.2 Risk Assessment and Screening

Women with DM should undergo regular breast cancer screening due to their elevated risk. Conversely, breast cancer patients with DM should be monitored for metabolic complications during and after treatment (Peairs et al., 2011).

7.4.3 Patient Education and Support

Educating patients about the links between DM and breast cancer empowers them to make informed decisions about lifestyle modifications and treatment options. Support groups and counseling services can address psychological and emotional challenges associated with managing both conditions.

Conclusion of Section 7

The prevention and management of DM and breast cancer require an integrative approach that addresses shared risk factors, optimizes pharmacological interventions, and leverages emerging therapeutic strategies. Lifestyle modifications, combined with innovative therapies targeting shared molecular pathways, hold great promise for reducing the burden of these diseases. Multidisciplinary care models and personalized treatment plans are essential to improving outcomes for patients affected by both DM and breast cancer.

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