Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy.
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.
Phoenix
Kathryn N
KN
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3501, USA.
Vumbaca
Frank
F
Fox
Melissa M
MM
Evans
Rebecca
R
Claffey
Kevin P
KP
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054392:Adipokines / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D039481:CD11b Antigen / Q000378:metabolism; D031204:Caloric Restriction; D045744:Cell Line, Tumor; D004032:Diet / Q000009:adverse effects*; D002149:Energy Intake; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D054392:Adipokines; D000970:Antineoplastic Agents; D015415:Biomarkers; D001786:Blood Glucose; D039481:CD11b Antigen; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D055372:AMP-Activated Protein Kinases