An inverse association exists between physical activity and breast cancer incidence and outcomes. An objective indicator of an individual’s recent physical activity exposure is aerobic capacity. We took advantage of the fact that there is an inherited as well as inducible component of aerobic capacity to show that experimentally induced mammary cancer is inversely related to inherent aerobic capacity (IAC). The objective of this study was to determine whether cell signaling pathways involved in the development of mammary cancer differed in rats with low inherent aerobic capacity (LIAC, n
= 55) versus high inherent aerobic capacity (HIAC, n
= 57). Cancer burden was 0.21 ± 0.16 g/rat in HIAC versus 1.14 ± 0.45 in LIAC, p
< 0.001. Based on protein expression, cancer in LIAC animals was associated with upregulated glucose utilization, and protein and fatty acid synthesis. Signaling in cancers from HIAC rats was associated with energy sensing, fatty acid oxidation and cell cycle arrest. These findings support the thesis that pro-glycolytic, metabolic inflexibility in LIAC favors not only insulin resistance and obesity but also tumor development and growth. This provides an unappreciated framework for understanding how obesity and low aerobic fitness, hallmarks of physical inactivity, are associated with higher cancer risk and poorer prognosis.
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