This competitive renewal grant application is based on our recent discovery that aerobic capacity, which has a heritable component, is strongly inversely associated with the occurrence of experimentally-induced breast cancer. Low aerobic capacity rats (LCR) had a 5.9-fold greater risk for breast cancer compared with high aerobic capacity rat (HCR) (OR: 5.90, 95% CI, 2.35-14.82). Subsequent molecular analyses revealed marked suppression of protein kinase A (PKA) phosphorylation and of several of its downstream targets including Src, signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt) and cAMP response-element binding protein (CREB) in mammary glands and tumors of HCR vs. LCR rats. This proposal builds on these observations to gain insights about how: (1) aerobic capacity, and (2) exercise training impact risk of breast cancer, and (3) whether effects on carcinogenesis are mediated in part via regulation of PKA and its downstream targets. Two aims are proposed: Aim 1 Determine the effect of aerobic exercise, in the presence or absence of a training effect, on mammary carcinogenesis in LCR and HCR rats. We will determine the effect(s) on the carcinogenic response and cellular and molecular mechanisms of aerobic exercise training: a) that increases aerobic capacity of LCR rats to the aerobic capacity of sedentary HCR rats, but that has no effect of the aerobic capacity of HCR rats, b) that induces the same percent increase in aerobic capacity in LCR and HCR rats, and c) that induces no change in aerobic capacity in LCR or HCR rats, i.e. the effect of exercise in the absence of a training effect. Mechanistic studies will identify the cellular process (es) (cell proliferation, apoptosis and/or angiogenesis) to which effects on carcinogenesis are linked, determine whether PKA mediates the observed effects on these processes, and investigate how changes in protein kinase A are mediated. Chemical agonists/antagonists administered locally via cannulation of the mammary gland lactiferous duct or systemically and gene knock down targeting PKA will be used to investigate causality. Aim 2 Determine exercise-aerobic capacity-cancer dose responses in LCR and HCR rats. Our hypothesis is that exercise-aerobic capacity-cancer dose responses will differ in LCR and HCR under varying exercise intensity (low, intermediate, and high) when rats are allowed to run without limitation. This aim extends our work to exercise conditions beyond those that increase aerobic capacity and examines the question, "if some exercise is good, is more better"? Evidence of linear and J-shaped hormetic dose responses will be assessed. Mechanistic studies will investigate the role of systemic and local effects such as ß-adrenergic regulated lipolysis that is mediated by PKA, recognizing the role of lipolysis in supporting extended periods of exercise. Paralleling Aim 1, chemical agonists and antagonists and genetic manipulations targeting ß-adrenergic receptor mediated signaling will be used to examine causal relationships.