The Renin-Angiotensin System, High Inherent Aerobic Capacity, and Low Breast Cancer Risk

Purpose: Physical activity is associated with reduced breast cancer risk. Aerobic capacity, which is the ability to generate and use energy on a sustained basis, has been hypothesized as a mechanism linking physical activity and cancer. Using selectively bred rats with distinctly different inherent aerobic capacity (IAC) in concert with a well-characterized model of breast cancer, we have previously reported that high IAC is protective against chemically induced mammary carcinogenesis. The mechanism(s) by which differing IAC confers effects on cells that reside in the mammary gland is unknown. Methods: To address this knowledge gap, RNA sequence analysis was performed on skeletal muscle, uninvolved mammary gland, and mammary carcinoma from rats of low or high IAC status. Results: Investigation of effects on upstream regulators led to a focus on the role of the renin-angiotensin system (RAS) in mediating effects on downstream targets relevant to the development of breast cancer. Patterns of RAS gene expression in skeletal muscle and mammary gland of high versus low IAC were consistent with counter-regulatory RAS activity signaling promoting anti-cancer biological functions while an opposite expression pattern of these transcripts was observed in tumor tissue. Conclusions: This study found a biologically plausible heritable relationship linking mechanisms associated with aerobic capacity and the development of breast cancer. Through RNA-seq analyses, we identified AGT as a biomarker pointing to differences in the regulation of RAS as a candidate mediator linking aerobic capacity and breast cancer. RNA sequence analysis was performed on skeletal muscle, uninvolved mammary gland, and mammary carcinoma from rats of low or high IAC status.