Metformin Activity against Breast Cancer: Mechanistic Differences by Molecular Subtype and Metabolic Conditions
Metformin [Working Title]
Obesity and type 2 diabetes increase the risk of and reduce survival in breast cancer (BC) patients. Metformin is the only anti-diabetic drug that alters this risk, with a reduction in BC incidence and improved outcomes. Metformin has AMP-kinase (AMPK) dependent and independent mechanisms of action, most notably affecting the liver and skeletal muscle. We and others have shown that metformin also downregulates protein and lipid synthesis; deactivates various receptor tyrosine kinases; alters
... kinases; alters cell cycle transcription/translation; modulates mitochondrial respiration and miRNA activation; targets key metabolic molecules; induces stem cell death and may induce apoptosis or autophagy in BC cells. Many of these anti-cancer effects are molecular subtype-specific. Metformin is most potent against triple negative (basal), followed by luminal BCs. The efficacy of metformin, as well as dose needed for the activity, is also modulated by the extracellular glucose concentration, cellular expression of the glucose transporter protein 1 (GLUT1), and the organic cation transporter protein 1 (OCT1, which transports metformin into cells). This chapter summarizes the diverse clinical and preclinical data related to the anti-cancer effects of metformin, focused against breast cancer. Metformin 2 facilitate cancer growth and survival  . More specifically, it may increase intracellular reactive oxygen species by disruption of the mitochondrial electron transport chain to reduce the mitochondrial membrane potential in BC or act directly to inhibit the mitochondrial respiratory-chain complex 1 (MRCC1)    . Chronic energy excess and physical inactivity lead to systemic alterations of carbohydrate and fatty acid metabolism characterized by systemic hyperglycemia, hyperinsulinemia with insulin resistance followed by hypoinsulinemia, an increase in inflammatory cytokines and adipokines, alterations of steroid and growth hormones, and downregulation of immune surveillance and tissue oxygenation [3, 9, 10] . These changes are frequent but variable in patients with obesity and type 2 diabetes and can be modified by drugs, exercise, body weight, socioeconomic factors, access to healthcare, genetic risk, and other factors. Patients with these disorders are at an increased risk of cardiovascular disease, cancer, and other diseases associated with significant morbidity and mortality. In the U.S., there are ~13.8 million type 2 diabetics, 5 million undiagnosed diabetics, and 41 million persons with prediabetes/metabolic syndrome    . Obesity is a frequent comorbidity, often proceeding diabetes by years or decades. Energy-sensing systems are integral to maintaining homeostasis in normal and transformed cells. Energy deprivation is frequent in cancer cells due to an inadequate vascular supply to meet the needs of increased cell replication. In energy-stressed cells, AMPK is allosterically modified by binding to AMP and ADP, rendering them targetable by AMPK kinases. AMPK activation induces signaling, upregulates energy production, and inhibits energy programming for cell growth and motility. In cancerous cells, this shift often fails to occur even with stress. As a result, cancer cells typically prioritize replication and motility to favor cancer growth and metastasis. Drugs that activate AMPK, most notably metformin, reengage the AMPK failsafe to inhibit proliferation and motility. Thus, metformin provides a unique and generally less-toxic approach to combat the emergence or growth of cancers through inhibition of cell replication. This is particularly important for patients with obesity and type 2 diabetes, who lack homeostasis and experience wide swings in systemic glucose, insulin, and other energy precursors and growth factors that contribute to systemic energy stress. Metabolic dysregulation, breast cancer, and metformin Abundant epidemiologic and clinical data have shown that obesity and type 2 diabetes increase the risk and severity of cardiovascular disease and human cancer. Each of these chronic metabolic disorders as a single variable significantly increases the risk of breast cancer (BC) [10, 14] . In combination, the risk is increased by 20-50%, depending on the severity of disease and other variables. It is highest in women with abdominal (central) obesity in the postmenopausal setting, in women of all ethnic backgrounds    . Obesity also promotes BC in premenopausal women of color, especially African Americans and Latinos       . In patients with obesity and diabetes, BC also presents at a higher disease stage and is more resistant to treatment, resulting in a shorter disease-free interval and a significantly higher mortality rate [24, 25] . Steroid receptor-positive BC (luminal A) and basal (triple negative) BC cells are the most responsive to extracellular glucose at or above 7 mM of glucose to promote cell replication, tumor growth, and motility. In contrast, steroid receptor-positive BC cells that also express high HER2 (luminal B) and steroid receptor-negative, HER2 positive (the HER2 subtype) are less responsive to hyperglycemia, even at levels associated with untreated type 2 diabetes (10 mM glucose or higher)  .