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Breast cancer is now the leading cause of cancer mortality among women worldwide, with more that 40,000 American women dying from the disease annually. While these statistics are grim, numerous epidemiological studies generally support a protective effect of physical activity for breast cancer. Animal data using voluntary wheel running and invasive cancer models are in line with human epidemiological data suggesting that physical exercise has anti tumor affects and may be associated with an increase in reactive oxygen species (ROS). Elevated production of mitochondrial ROS (mtROS) is also associated with the promotion of tumor progression, and attenuation of oxidative stress with a mitochondrial targeted antioxidant has been shown to reduce tumor burden and metastasis in an invasive breast cancer mouse model. However, if an anti-tumor effect of running is associated with an increase in ROS, then there is a potential paradox in that any anti-oxidant activity directed to mitochondria might mitigate ROS and prevent anti-tumor affects.