Abstract
Aerobic capacity, which is synonymous with the term cardiorespiratory fitness, is a strong inverse predictor of breast cancer mortality, yet the underlying mechanisms are poorly understood. In this study, RNA sequence data were used to interrogate the tumor microenvironment for potential etiological clues in a rodent model for breast cancer, widely regarded to have similar histogenesis and pathogenesis as the human disease, including about 70 percent of the tumors being ovarian hormone-responsive mammary carcinomas. What was novel about our approach is that tumor microenvironment gene expression profiles were contrasted between genetically distinct sedentary rats selectively bred to have low vs. high inherent aerobic capacity. Inherent aerobic capacity is generally overlooked as a variable in human populations, yet the observed range exceeds three-fold. RNA sequence analysis was performed on mammary carcinomas and adjacent uninvolved mammary glands, i.e., the tumor microenvironment. Investigation of effects on canonical signaling pathways, upstream regulators, and downstream effectors identified differentially expressed transcriptional signatures within the renin-angiotensin system, interferon gamma, and nitric oxide signaling pathways, distinguishing between low or high inherent aerobic capacity in the tumor microenvironment. Within these pathways, master upstream regulators: interferon gamma, interleukin-1 beta, tumor necrosis factor, and angiotensinogen emerged as part of a complex network reflecting inherent aerobic capacity-related differences, which were accompanied by differences in immune cell populations present within the tumor microenvironment. The data support the potential value of inherent aerobic capacity phenotyping in the development of precision approaches to breast cancer treatment.