Abstract
Metformin is the most widely administered anti-diabetic agent worldwide. In patients receiving metformin for metabolic syndrome or diabetes, it reduces the incidence and improves the survival of breast cancer (BC) patients. We have previously shown that metformin is particularly potent against triple negative breast cancer (TNBC), with a reduction of proliferation, oncogenicity and motility, inhibition of pro-oncogenic signaling pathways and induction of apoptosis. These BCs are well recognized to be highly dependent on glucose/glucosamine (metabolized through anaerobic glycolysis) and lipids, which are metabolized for the production of energy and cellular building blocks to sustain a high rate of proliferation. We have previously demonstrated that metformin inhibits lipid metabolism, specifically targeting fatty acid synthase (FASN), cholesterol biosynthesis and GM1 lipid rafts in TNBC. We also reported that glucose promotes phenotypic aggression and reduces metformin efficacy. We now show that metformin inhibits several key enzymes requisite to glucose metabolism in TNBC, providing additional insight into why metformin is especially toxic to this subtype of BC. Our data suggests that the use of metformin to target key metabolic defects in lipid and carbohydrate metabolism in cancer may be broadly applicable, especially against highly aggressive malignant cells.
Highlights
Breast cancer (BC) morbidity and mortality remain stubbornly high worldwide, despite the fact that disease characteristics vary by geography, ethnicity, age, body mass and other factors
While the prognosis for breast cancer (BC) patients is better in the US than in much of the world, our incidence of disease is especially high in women with obesity and type II diabetes/ metabolic syndrome
We have shown that the mechanisms of metformin action vary by molecular subtype of the disease [58,59,60,61], and that triple negative breast cancer (TNBC) are especially sensitive to its anti-cancer effects
Summary
Breast cancer (BC) morbidity and mortality remain stubbornly high worldwide, despite the fact that disease characteristics vary by geography, ethnicity, age, body mass and other factors. Metabolic syndrome and type II diabetes are associated with systemic dysregulation of lipid and carbohydrate metabolism These changes disrupt a broad array of cell types and put the patient at an increased risk of cardiovascular disease and cancer [29]. We have shown that metformin had significant antitumor effects in this rodent model These findings suggest a basis for the epidemiological and data indicating that in patients with metabolic syndrome or type II diabetes, metformin treatment reduces cancer incidence and improves survival for patients that develop the disease (in stark contrast to other anti-cancer agents including insulin that increases BC risk) [34,35,36]. Reduction of LDH by genetic manipulation or the chemical inhibitor oxamate have reversed of taxolresistance and induced apoptosis in BC cells [66]
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