Physical Activity and Postmenopausal Breast Cancer: Proposed Biologic Mechanisms and Areas for Future Research

Abstract

Convincing evidence now supports a probable preventive role for physical activity in postmenopausal breast cancer. The mechanisms by which long-term physical activity affect risk, however, remain unclear. The aims of this review were to propose a biological model whereby long-term physical activity lowers postmenopausal breast cancer risk and to highlight gaps in the epidemiologic literature. To address the second aim, we summarized epidemiologic literature on 10 proposed biomarkers, namely, body mass index (BMI), estrogens, androgens, sex hormone binding globulin, leptin, adiponectin, markers of insulin resistance, tumor necrosis factor-A, interleukin-6, and C-reactive protein, in relation to postmenopausal breast cancer risk and physical activity, respectively. Associations were deemed ''convincing,'' ''probable,'' ''possible,'' or ''hypothesized'' using set criteria. Our proposed biological model illustrated the co-occurrence of overweight/obesity, insulin resistance, and chronic inflammation influencing cancer risk through interrelated mechanisms. The most convincing epidemiologic evidence supported associations between postmenopausal breast cancer risk and BMI, estrogens, and androgens, respectively. In relation to physical activity, associations were most convincing for BMI, estrone, insulin resistance, and C-reactive protein. Only BMI and estrone were convincingly (or probably) associated with both postmenopausal breast cancer risk and physical activity. There is a need for prospective cohort studies relating the proposed biomarkers to cancer risk and for long-term exercise randomized controlled trials comparing biomarker changes over time, specifically in postmenopausal women. Future etiologic studies should consider interactions among biomarkers, whereas exercise trials should explore exercise effects independently of weight loss, different exercise prescriptions, and effects on central adiposity.

Physical Activity and Genitourinary Cancer Survivorship

“…Epidemiologic evidence supports a positive association between serum androgen levels and postmenopausal (Key et al 2002;Neilson et al 2009) and, to a lesser extent, premenopausal breast cancer risk (Eliassen and Hankinson 2008). In a pooled analysis of prospective studies, postmenopausal women in the highest quintiles of serum testosterone and androstenedione concentrations, respectively, had more than double the risk of developing breast cancer compared to women in the lowest quintiles (RR = 2.22, 95% CI: 1.59-3.10 for testosterone; RR = 2.15, 95% CI: 1.44-3.21 for androstenedione) (Key et al 2002).…”

“…Various biologic pathways relating physical activity to breast cancer risk have been proposed (McTiernan 2008;Neilson et al 2009;Rogers et al 2008;Thompson et al 2009;…”

“…One currently hypothesized biologic model for breast cancer risk, focusing mainly on the promotion and progression of initiated cells, implicates sex hormones, insulin resistance, adipokines, and chronic inflammation as possible mediators of physical activity (Neilson et al 2009) (Fig. 2.12).…”

“…The effect may vary according to menopausal status. Yet within pre-and postmenopausal women, relations between breast cancer risk and insulin or C-peptide have been inconsistent (Neilson et al 2009;Xue and Michels 2007). Recently, however, one cohort study of 5,450 postmenopausal women that employed serial measurements of glucose and insulin found a statistically significant positive association between breast cancer risk and insulin levels (Kabat et al 2009) and a case-cohort study found the same association but only amongst nonusers of hormone therapy (Gunter et al 2009).…”

“…Perpetual cell proliferation, microenvironmental changes and oxidative stress resulting from chronic inflammation could deregulate normal cell growth to promote initiated cells toward malignancy (Coussens and Werb 2002). Adipokines may also increase risk on account of their strong positive correlations with hyperinsulinemia, insulin resistance, and type 2 diabetes, by affecting estrogen biosynthesis and estrogen activity, or by directly altering cell growth and promoting metastases (reviewed in, Neilson et al 2009). …”