Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy

Abstract

Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.

Increased efficacy of metformin corresponds to differential metabolic effects in ovarian tumors in obese versus lean mice

“…Animal studies in other cancers have also evaluated the relationship between obesity and efficacy of metformin and found similar results to ours [76][77][78]. In particular, in both lung and breast cancer animal models, metformin was found to be more effective in decreasing tumor growth in animals fed a HFD compared to a low fat or standard diet [79,80]. Furthermore, in a randomized, placebo-controlled preoperative window study in breast cancer patients, women with higher body mass index (BMI) and Homeostatic Model Assessment of Insulin Resistance (HOMA) indexes had a greater response to metformin as evidenced by a decrease in Ki-67 staining [81].…”

The ketogenic diet for the treatment of malignant glioma

“…In 1914, Payton Rous was the fi rst to suggest that restricted food intake reduced tumor growth by reducing the tumor blood supply ( 42 ). More recently, it has been suggested that CR reduces growth and angiogenic biomarker expression in prostate cancer and breast cancer (43)(44)(45)(46). The combination of CR and the KD [calorie restricted KD (RKD)] has also been studied as a cancer therapy.…”

Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism

“…Conversely, Metformin (a mitochondrial complex I inhibitor) 47 should prevent cancer cells from effectively using mitochondrial fuels by inhibiting OXPHOS in cancer cells, inducing the conventional Warburg effect in cancer cells. [48][49][50][51][52] In fact, all three drugs have been shown to function as anticancer agents and also are associated with increased lifespan in studies of longevity. [53][54][55][56][57][58][59][60][61][62][63][64][65][66] So, a global whole-body approach to normalizing energy balance may prevent both aging and cancer, simultaneously.…”