Linking Physical Activity to Breast Cancer via Sex Steroid Hormones, Part 2: The Effect of Sex Steroid Hormones on Breast Cancer Risk

Drummond, Ann E.; Swain, Christopher T.V.; Brown, Kristy A.; Dixon-Suen, Suzanne C.; Boing, Leonessa; Roekel, Eline H. van; Moore, Melissa M.; Gaunt, Tom R.; Milne, Roger L.; English, Dallas R.; Martin, Richard M.; Lewis, Sarah J.; Lynch, Brigid M.

doi:10.1158/1055-9965.epi-21-0438

Cited by 33 publications

(29 citation statements)

References 92 publications

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“…Four additional steroids, DHEA-S, androsteroid monosulfate [ 1 ], androstenediol (3β,17β) disulfate [ 2 ], and androstenediol (3β,17β) monosulfate [ 1 ], were also associated with an increased risk of breast cancer in CPS-3. These results, as well as the finding that the associations were only with postmenopausal breast cancer, are consistent with findings from other studies of circulating steroids [ 23 – 25 ]. Most studies of steroid metabolites in breast cancer have focused on androgens such as DHEA as the key metabolites influencing estrogen metabolism [ 26 ].…”

Section: Discussionsupporting

confidence: 92%

A prospective case–cohort analysis of plasma metabolites and breast cancer risk

et al. 2023

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Background Breast cancer incidence rates have not declined despite an improvement in risk prediction and the identification of modifiable risk factors, suggesting the need to identify novel risk factors and etiological pathways involved in this cancer. Metabolomics has emerged as a promising tool to find circulating metabolites associated with breast cancer risk. Methods Untargeted metabolomic analysis was done on prediagnostic plasma samples from a case–cohort study of 1695 incident breast cancer cases and a 1983 women subcohort drawn from Cancer Prevention Study 3. The associations of 868 named metabolites (per one standard deviation increase) with breast cancer were determined using Prentice-weighted Cox proportional hazards regression modeling. Results A total of 11 metabolites were associated with breast cancer at false discovery rate (FDR) < 0.05 with the majority having inverse association [ranging from RR = 0.85 (95% CI 0.80–0.92) to RR = 0.88 (95% CI 0.82–0.94)] and one having a positive association [RR = 1.14 (95% CI 1.06–1.23)]. An additional 50 metabolites were associated at FDR < 0.20 with inverse associations ranging from RR = 0.88 (95% CI 0.81–0.94) to RR = 0.91 (95% CI 0.85–0.98) and positive associations ranging from RR = 1.13 (95% CI 1.05–1.22) to RR = 1.11 (95% CI 1.02–1.20). Several of these associations validated the findings of previous metabolomic studies. These included findings that several progestogen and androgen steroids were associated with increased risk of breast cancer in postmenopausal women and four phospholipids, and the amino acids glutamine and asparagine were associated with decreased risk of this cancer in pre- and postmenopausal women. Several novel associations were also identified, including a positive association for syringol sulfate, a biomarker for smoked meat, and 3-methylcatechol sulfate and 3-hydroxypyridine glucuronide, which are metabolites of xenobiotics used for the production of pesticides and other products. Conclusions Our study validated previous metabolite findings and identified novel metabolites associated with breast cancer risk, demonstrating the utility of large metabolomic studies to provide new leads for understanding breast cancer etiology. Our novel findings suggest that consumption of smoked meats and exposure to catechol and pyridine should be investigated as potential risk factors for breast cancer.

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Section: Discussionsupporting

confidence: 92%

A prospective case–cohort analysis of plasma metabolites and breast cancer risk

et al. 2023

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“…In this review, we aim to synthesize and appraise the evidence for an effect of physical activity on each of these sex hormones. The review of the evidence for the latter step assessing the putative pathway of interest is published concurrently ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones

Swain

Drummond

Boing

et al. 2021

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity–sex hormone–breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer.

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“…There is substantial evidence for multiple mechanisms, 45 and although exact mechanisms are currently unclear, several pathways linking physical activity to premenopausal breast cancer risk have been proposed. 46,47 Some evidence suggests that physical activity causes reduced levels of sex steroid hormones such as estrogens and androgens, [48][49][50] which could mediate an effect on breast cancer risk. Additionally, the impact of physical activity on decreasing fasting insulin levels and insulin/insulin-like growth factor signaling could also drive breast cancer risk, 51 including through a direct effect on tumor growth.…”

Section: Discussionmentioning

confidence: 99%

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts

Timmins,

Jones,

O'Brien

et al. 2024

JCO

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PURPOSE There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2–enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

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Linking Physical Activity to Breast Cancer via Sex Steroid Hormones, Part 2: The Effect of Sex Steroid Hormones on Breast Cancer Risk

Cited by 33 publications

References 92 publications

A prospective case–cohort analysis of plasma metabolites and breast cancer risk

A prospective case–cohort analysis of plasma metabolites and breast cancer risk

Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts

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