Candidate mechanisms accounting for effects of physical activity on breast carcinogenesis

Abstract

Evidence is strong that a reduction in risk for breast cancer is associated with moderate to vigorous physical activity (PA); however, there is limited understanding of the role of type, intensity, duration, and frequency of PA and their mechanisms in accounting for this health benefit. The objective of this review is to stimulate investigations of candidate mechanisms that may account for the effects of the intensity and duration of aerobic PA on breast cancer risk and tumor burden. Three hypotheses are considered: 1) the mTOR network hypothesis: PA inhibits carcinogenesis by suppressing the activation of the mTOR signaling network in mammary carcinomas; 2) the hormesis hypothesis: the carcinogenic response to PA is non linear and accounted for by a physiological cellular stress response; and 3) the metabolic reprogramming hypothesis: PA limits the amount of glucose and glutamine available to mammary carcinomas thereby inducing apoptosis because tumor-associated metabolic programming is reversed. To link these hypotheses to systemic effects of PA, it is recommended that consideration be given to determining : 1) what contracting muscle releases into circulation or removes from circulation that would directly modulate the carcinogenic process in epithelial cells; 2) whether the effects of muscle contraction on epithelial cell carcinogenesis are exerted in an endocrine, paracrine, autocrine, or intracrine manner; and 3) if the effects of muscle contraction on malignant cells differ from effects on normal or pre-malignant cells that do not manifest the hallmarks of malignancy.

Recent Recreational Physical Activity and Breast Cancer Risk in Postmenopausal Women in the E3N Cohort

“…The lack of significant change in associations according to ER subtype or after adjustment for BMI suggests that the mechanisms involved are also nonhormonal; they might thus include decreased inflammation (34), immunomodulation (34), interference with the glycolytic switch (35), or decreased DNA damage (34). Physical activity also improves insulin sensitivity independently of changes in body weight or composition (34): it decreases estradiol bioavailability by increasing SHBG levels (1).…”

IGF-1 Mediates Exercise-Induced Phospholipid Alteration in the Murine Skin Tissues

“…However, the underlying mechanisms have not been fully elucidated. Several proposed hypotheses include DNA repair, apoptosis regulation, oncogene inhibition and hormone alteration [8]. Alterations of the growth factor IGF-1-related signaling pathway seem to be one of the key mechanisms for weight-loss related cancer prevention.…”

Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

“…In fact, we have previously shown that treadmill exercise can reduce circulating levels of the inflammatory, pro-tumorigenic cytokines, MCP-1 and IL-6, in accordance with decreased tumor volume in C3(1)/SV40Tag mice (15). Further, exercise induced changes in the availability of metabolic fuels, due at least in part to decreased tumor blood flow, may limit tumor growth in this mouse model (31). Future studies should focus on investigating the effects of exercise on these mechanisms specifically in the C3(1)/SV40Tag mouse.…”

“…In support of our findings, several other investigations have also shown benefits of physical activity on breast cancer independent of changes in body composition (5,9,10). Therefore, additional hypotheses explaining the changes induced by voluntary wheel running may include alterations in energy sensing pathways, growth related proteins and/or myokines and cytokines (14,15,31). In fact, we have previously shown that treadmill exercise can reduce circulating levels of the inflammatory, pro-tumorigenic cytokines, MCP-1 and IL-6, in accordance with decreased tumor volume in C3(1)/SV40Tag mice (15).…”