Physical Activity and Breast Cancer: Review of the Epidemiologic Evidence and Biologic Mechanisms
Breast cancer is the most commonly diagnosed invasive malignancy and the second leading cause of cancer death in women globally. This review considers epidemiologic evidence regarding the association between physical activity and breast cancer risk. Across these studies there was a 25% average risk reduction among physically active women as compared to the least active women. The associations were strongest for recreational activity, for activity sustained over the lifetime or done after menopause, and for activity that is of moderate to vigorous intensity and performed regularly. There is also some evidence for a stronger effect of physical activity among postmenopausal women, women who are normal weight, have no family history of breast cancer, and are parous. It is likely that physical activity is associated with decreased breast cancer risk via multiple interrelated biologic pathways that may involve adiposity, sex hormones, insulin resistance, adipokines, and chronic inflammation. Future research should include prospective observational epidemiologic studies relating proposed biomarkers to breast cancer risk and also randomized controlled trials to examine how physical activity influences the proposed biomarkers. Exercise trials will provide more clarity regarding the appropriate type, dose, and timing of activity that are related to breast cancer risk reduction.
Breast cancer remains a leading cause of cancer incidence and mortality in most developed countries worldwide. While significant international research has examined risk factors for breast cancer, most identified risk factors are nonmodifiable. During the past 20 years, over 90 studies have been conducted worldwide that have examined some aspects of the association between physical activity and breast cancer risk reduction. The purpose of this chapter is to review both the epidemiologic evidence and hypothesized biologic mechanisms whereby physical activity may influence breast cancer risk.
11.1 Epidemiologic Evidence
Previous reviews on physical activity and breast cancer prevention have generally concluded that the evidence supporting this association is “convincing” (Friedenreich and Cust 2008; Friedenreich and Orenstein 2002; IARC Working Group 2002; Monninkhof et al. 2007a) or at least “probable” (World Cancer Research Fund and the American Institute for Cancer Research 2007). The current review paper summarizes a more detailed review just completed (Lynch et al. 2010) that incorporates 33 cohort studies and 40 case–control studies identified by February 2010 and excludes duplicate publications from the same studies.
11.1.2 Methodologic Issues in Studies of Physical Activity and Cancer
Inherent in the studies of physical activity and cancer is the difficulty in assessing usual physical activity over lifetime. A wide range of definitions of physical activity has been used in previous studies as they have not uniformly assessed all types of activity (i.e., occupational, household, and recreational), the dose of activity (frequency, intensity, and duration), or all time periods in life when activity was performed. Besides the difficulty in assessing physical activity, the adjustment for confounders and the assessment of effect modification by other factors or characteristics of the study population has varied considerably across these studies. Given these limitations, a formal meta-analysis of the published results cannot be undertaken since uniform exposure assessments have not been done across these observational studies.
11.1.3 Overall Associations Between Physical Activity and Breast Cancer Risk
11.1.4 Type, Dose, and Timing of Activity
Physical activity has a beneficial effect on breast cancer risk when performed at any age throughout life, but activity done after age 50 does have a stronger effect on risk than activity done earlier in life. After age 50, average risk reductions of 17% were found in those studies that measured activity during this age period and this level of risk reduction decreased to 8% for activity done earlier in adulthood.
11.1.5 Population Subgroups
Given the large number of studies that have been conducted on physical activity and breast cancer, it is also possible to consider how this association may vary across different population subgroups. This type of information may be of particular use when designing tailored public health recommendations for particular populations regarding the benefits of physical activity for their breast cancer risk reduction. Effect modification by menopausal status, body mass index (BMI; weight/height2) race, family history of breast cancer, hormone receptor status, and parity were considered.
Breast cancer risk decreases in both pre and postmenopausal women, however, the average risk reduction is somewhat greater for postmenopausal women (31%) than among premenopausal women (27%). In studies that stratified their results by menopausal status, only three of 25 studies observed statistically significant decreases in breast cancer risk for both pre and postmenopausal women (Lynch et al. 2010). In 25 other studies that included either pre or postmenopausal women only, 13 studies found greater risk reductions among postmenopausal women, 11 studies found a stronger effect among premenopausal women, and one study found no difference by menopausal status (Lynch et al. 2010). It is noteworthy, however, that of these 25 studies stratified by menopausal status, 12 yielded statistically significant risk reductions in postmenopausal women, whereas only three studies showed statistically significant risk reductions in premenopausal women.
Effect modification by BMI was examined in 22 studies (Lynch et al. 2010). Physical activity had the greatest impact on breast cancer prevention among women with a lean BMI (<22) for whom the average risk reduction was 27%. For normal weight women (BMI = 22–24.9), the average risk reduction for higher physical activity levels was 24%, for overweight women (BMI = 25.0–29.9) was 18%, and for obese women (BMI > 30.0) was less than 1%.
Physical activity exerts a beneficial effect on all racial and ethnic groups but a somewhat stronger effect has been observed in Asian women (average relative decrease of 41%) and black women (average 41%), followed by Indian women (average 38%), Hispanic women (average 28%), and white women (20%).
Only nine studies have considered whether or not family history of breast cancer influences how physical activity impacts breast cancer risk (Lynch et al. 2010). Eight of these nine studies did find evidence for effect modification by family history of breast cancer. In those studies, physical activity had a much greater benefit for women without a family history of breast cancer as compared to those with a family history since average risk reductions of 21% versus less than 1% were found, respectively, for these two groups.
Estrogen and progesterone receptor (ER, PR) status was examined in 11 studies as a potential effect modifier (Lynch et al. 2010). No clear pattern of effect modification by hormone receptor status is yet evident from these studies. More evidence for an effect of physical activity on ER+ or PR+ tumors was found than for ER- or PR-tumors when these receptors are examined separately. However, when the combined hormone receptor status was considered, statistically significant risk reductions were found in only one ER+/PR+ study and one ER-/PR- study. Average risk reductions were greater for women with ER-/PR- tumors (27%) than for women with ER+/PR+ tumors (14%).
Effect modification by parity was examined in only seven studies with a greater risk reduction found among physically active parous women (average decrease in breast cancer risk 38%) than nulliparous women (average decrease 18%).
11.1.6 Summary of Epidemiologic Findings
A review of the epidemiologic findings for physical activity and breast cancer is limited by the heterogeneous activity assessment methods used, the variable study quality, and reporting of study results which compromises the ability to make direct comparisons across studies. This narrative review was restricted to using crude averages of risk reductions as a means of evaluating the magnitude of the effect of physical activity on breast cancer risk.
With these limitations in mind, a conservative estimate of the effect of physical activity and breast cancer risk is a 25% decrease in risk for physically active women. When examining the effect by type, dose, and timing of activity, the greatest reductions are found for recreational and household activities, for activities of longer duration, of at least moderate intensity, and for activity done after menopause. However, risk reductions were apparent for all types of activity, for lower doses of activity and for activity undertaken across the entire lifespan. The effect of physical activity on breast cancer risk is also somewhat stronger for postmenopausal women, for all body sizes with the exception of obese women, for women of non-Caucasian backgrounds, for women without a family history of breast cancer and for parous women. There was no clear effect modification of the association between physical activity and breast cancer risk by hormone receptor status.
Given the consistency, strength, and evidence for dose–response that has been observed in these epidemiologic studies, an argument has been made that randomized controlled exercise intervention trials (RCTs) are now needed to advance understanding of how physical activity influences breast cancer (Friedenreich 2001). Three intervention trials have been conducted to date in postmenopausal women who are free of breast cancer to examine how aerobic exercise affects the biologic mechanisms that are hypothesized to be part of the pathway between physical activity and breast cancer risk (Friedenreich et al. 2010a; McTiernan et al. 1999; Monninkhof et al. 2007b). These two-armed trials have each compared a supervised, aerobic exercise intervention to no activity in postmenopausal women. Body composition, metabolic and sex steroid hormones, growth factors, inflammation and insulin resistance biomarkers, and mammographic density were measured in each group to determine the impact of exercise on these biomarkers. These RCTs, known as the Physical Activity for Total Health (PATH) trial (n = 173) (McTiernan et al. 1999), the Sex Hormones and Physical Exercise (SHAPE) trial (n = 189) (Monninkhof et al. 2007b), and the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) trial (n = 320) (Friedenreich et al. 2010a), administered moderate- to vigorous-intensity physical activity interventions ranging from 150 to 225 min/week over 12 months. These studies have provided direct evidence on the effects of exercise on these biomarkers, with more published results anticipated in the future. The findings published to date are described in the relevant sections below in the full description of the hypothesized biologic mechanisms operating between physical activity and breast cancer risk.
11.2 Biologic Mechanisms
Several hypothesized 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; Wetmore and Ulrich 2006), but definitive evidence regarding these pathways has been emerging only recently. Given the multifactorial etiology of breast cancer, it is likely that many interrelated pathways are involved in reducing breast cancer risk. It is also possible that certain mechanisms predominate with specific doses or types of physical activity or perhaps in select subgroups of women, as presented earlier in this review. The primary hypotheses involve an impact of physical activity on adiposity, sex hormones, insulin resistance, adipokines, and inflammatory markers.
The role of adiposity as a mediator of the effect of physical activity on breast cancer risk is a central component of these hypothesized pathways because of the well-established association between weight, body fat levels, and weight gain and postmenopausal breast cancer risk (Renehan et al. 2008; World Cancer Research Fund and the American Institute for Cancer Research 2007). Physical activity may influence breast cancer risk through weight loss in overweight women or in weight maintenance in normal weight women (Donnelly et al. 2009; Lau et al. 2007) and there is emerging evidence that physical activity may achieve abdominal fat loss with the right exercise prescription (e.g., (Cuff et al. 2003; Giannopoulou et al. 2005; Irwin et al. 2003)). The PATH and ALPHA trials demonstrated a clear exercise effect in a range of body composition measures (Friedenreich et al. 2010b; Irwin et al. 2003) including abdominal fat, whereas the SHAPE trial found that exercisers decreased body fat and waist circumference, but not weight, in comparison to controls (Velthuis et al. 2009). Therefore, fat loss is a logical explanation for the association between exercise and postmenopausal breast cancer risk.
11.2.2 Sex Hormones
The role of endogenous estrogens in breast cancer etiology is well recognized since estrogens inhibit apoptosis, act as mitogens in the breast (Lorincz and Sukumar 2006; Yager and Davidson 2006), and antiestrogenic drugs are successfully used to treat women with ER+ breast tumors (Uray and Brown 2006). In addition, there is compelling evidence from observational studies for a positive association between breast cancer risk and estrogens in postmenopausal women. Estradiol and estrone have been clearly shown to double postmenopausal breast cancer risk (Key et al. 2002). Physical activity may impact on endogenous estrogen levels through several mechanisms: by reducing body fat levels (the main source of estrogen production after menopause); altering adipokine levels that influence estrogen production (Cleary and Grossmann 2009); and lowering blood insulin levels thereby increasing circulating sex hormone binding globulin (SHBG) (Kaaks 1996; Pugeat et al. 1991), which binds reversibly to estrogens to affect their bioavailability. In premenopausal women, it is hypothesized that physical activity may delay menarche, decrease ovulation, and increase amenorrhea, which would result in a lower lifetime exposure to endogenous estrogens and lowering of breast cancer risk (Bernstein 2009; Campbell and McTiernan 2007).
Breast cancer risk may also be affected by endogenous androgen levels since androgens can have a direct effect on breast cell growth (Nicolas Diaz-Chico et al. 2007) and an indirect effect via estrogen production since androgens can be converted to estrogens (Kendall et al. 2007). Observational studies have found an independent effect of testosterone on breast cancer risk even after adjustment for estradiol levels with a doubling in risk of breast cancer for women at the highest serum androgen levels (Kaaks et al. 2005; Key et al. 2002). As with estrogens, physical activity may lower testosterone levels by decreasing adiposity or by increasing SHBG levels via lowered blood insulin levels
Some evidence now exists from two RCTs that the effect of physical activity on sex hormones varies by changes in body fat. In the PATH and SHAPE trials, women randomized to the exercise group who lost more than 2% body fat experienced significantly lower blood estrogen levels compared with controls after 12 and 4 months of exercise, respectively (McTiernan et al. 2004a; McTiernan et al. 2004b; Monninkhof et al. 2009). In the ALPHA trial, estrogen levels decreased significantly more in exercisers than in controls after 12 months, even after adjusting for weight change suggesting a role for physical activity that is independent of adiposity changes (Friedenreich et al. 2010a). Similarly, some cross-sectional studies (Cauley et al. 1989; Chan et al. 2007; Madigan et al. 1998; Verkasalo et al. 2001), but not all (Bertone-Johnson et al. 2009; Van Gils et al. 2009) in postmenopausal women have found statistically significant inverse associations between physical activity and sex hormone levels even after controlling for BMI or adiposity. Hence, it is unclear if fat loss is a required prerequisite for sex hormone changes induced by physical activity.
11.2.3 Insulin-Related Factors
A pathway between insulin resistance and breast cancer risk has been hypothesized (Kaaks 1996) and several lines of evidence support this hypothesis. To begin, insulin has mitotic and antiapototic effects in breast cancer cells (Lann and LeRoith 2008; Osborne et al. 1976). Second, hyperinsulinemia decreases SHBG levels, which thereby increases the bioavailability of sex hormones (Kaaks 1996; Pugeat et al. 1991). Third, insulin resistance and hyperinsulinemia are also strongly related to obesity (Haslam and James 2005) and specifically intra-abdominal fat (Kaaks 1996) as well as various adipokines and inflammatory factors (Rose et al. 2004; Vona-Davis et al. 2007), which have all been associated with breast cancer risk. Hence, insulin may alter breast cancer risk independently or indirectly through other biomarkers of risk.
The epidemiologic evidence regarding the role of insulin in breast cancer risk is growing but remains inconclusive with some evidence for an increased breast cancer risk in women with type 2 diabetes (Larsson et al. 2007; Xue and Michels 2007) and inconsistent evidence for the association between breast cancer risk and insulin or C-peptide (Gunter et al. 2009; Kabat et al. 2009; Neilson et al. 2009; Pisani 2008; Xue and Michels 2007).
Exercise combined with weight loss is generally accepted as an effective means for improving insulin sensitivity and preventing diabetes (Ivy 1997; Klein et al. 2004; Ryan 2000; Warburton et al. 2007). In the PATH trial, insulin levels decreased with moderate exercise and the change in insulin level was greatest among exercisers who also lost >2 kg body fat over the year (Frank et al. 2005). In addition, among those women who gained body fat over the year, exercise prevented an increase in insulin levels. Hence, exercise appears to alter insulin levels through weight change and also independently of fat loss.
Insulin-like growth factor-1 (IGF-1) has been hypothesized to increase breast cancer risk since it has both a direct mitogenic and apoptotic effect on breast tissue (Yu and Rohan 2000). However, the epidemiologic evidence for a positive association with breast cancer is inconsistent (Eliassen and Hankinson 2008; Fletcher et al. 2005; Lann and LeRoith 2008) as is the association with physical activity on IGF-1 and IGF-binding protein-3 (IGFBP-3) (McTiernan et al. 2005; Orenstein and Friedenreich 2004; Tworoger et al. 2007b). Thus, the IGFs may not be important biologic mechanisms mediating the impact of physical activity on breast cancer risk.
11.2.4 Adipokines and Inflammation
Adipokines, specifically leptin, adiponectin, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are polypeptides produced by adipocytes that may increase breast cancer risk through direct mechanisms, through associations with insulin resistance or in some cases, by enhancing estrogen activity (Neilson et al. 2009). Inflammatory markers, including TNF-α and IL-6 and C-reactive protein (CRP), are all elevated with obesity, which is a chronic low-grade, systemic inflammatory state (Lee and Pratley 2005). Chronic inflammation is hypothesized to increase cancer risk by deregulating normal cell growth that can promote initiated cells to malignancy through its impact on increased cell proliferation, microenvironmental changes and oxidative stress (Coussens and Werb 2002).
Although biological plausibility exists for an etiologic role of adipokines in breast carcinogenesis, there is currently little epidemiologic evidence for an association between breast cancer risk and adipokines and inflammatory markers (Neilson et al. 2009). The evidence is somewhat stronger for adiponectin than for leptin but for both adipokines, the evidence remains limited (Barb et al. 2007; Cust et al. 2009; Stattin et al. 2004; Tworoger et al. 2007a).
Exercise trials conducted with various study populations have generally found no effect of exercise on inflammatory markers, however, conclusions regarding these associations are difficult to make because of the differing study designs and study populations (Wetmore and Ulrich 2006). The PATH trial found that a 12-month exercise intervention lowered leptin (Frank et al. 2005) and CRP (Campbell et al. 2009) levels, but CRP was decreased only among obese women or those with abdominal obesity who lost body fat. Other exercise RCTs have, however, achieved decreases in adipokine and CRP levels independent of fat loss (Balducci et al. 2009; You et al. 2004). Hence, it remains unclear if changes in adipokine and inflammatory markers are dependent on changes in body fat.
11.2.5 Other Mechanisms
Several other biologic mechanisms that cause DNA damage, cancer initiation, promotion, or progression have been hypothesized to explain how physical activity influences breast cancer risk (Rundle 2005). For some pathways, such as mammographic density, that have been strongly associated with breast cancer risk, there is no convincing evidence that exercise impacts these mechanisms (Atkinson et al. 2004; Campbell et al. 2007; Schmitz et al. 2008; Woolcott et al. 2010). Physical activity may impact breast cancer risk by decreasing oxidative stress (Dai et al. 2009; Schmitz et al. 2008), enhancing immune function (Campbell et al. 2008; Wetmore and Ulrich 2006), reducing promoter hypermethylation of tumor suppressor genes or by reducing genotoxicity from estrogen metabolite-DNA adducts formed in breast tissue (Coyle 2008). Exercise may also have a favorable effect on some intracellular signaling pathways by suppressing pro-carcinogenic pathways and promoting anticarcinogenic pathways (Thompson et al. 2009). Finally, genetic factors may also modify the effect of exercise on these biomarkers and may be important to consider when examining their etiologic role in the association between physical activity and breast cancer.
There is now strong and consistent evidence from 73 studies conducted worldwide that physical activity reduces breast cancer risk by about 25% and that a dose–response effect exists. Several plausible biologic mechanisms are emerging involving adiposity, sex and metabolic hormones, insulin, inflammation, and adipokines to explain this association. The evidence from randomized exercise intervention trials that have examined these biomarkers is particularly useful in understanding these associations. While all types of activities and different doses of activity appear to reduce breast cancer risk, somewhat stronger risk reductions are evident with recreational activity, activity that is at least of moderate intensity and performed regularly and that is sustained over lifetime or at least after menopause. Some evidence also exists now that physical activity may have a stronger effect in postmenopausal women, normal weight women, non-Caucasians, parous women, and women without a family history of breast cancer.
Future research in this field should examine how sedentary behavior and light-intensity activity are related to breast cancer risk. Improvements in quantifying physical activity with objective measurements as well as more precision regarding the type, dose, and timing of activity over lifetime is also needed for a better understanding of the nature of these associations. Future investigations of the effect modification of this association by other factors will clarify some of the complexity of these associations. There is also a need for prospective observational epidemiologic studies relating new and proposed biomarkers to breast cancer risk and additional randomized controlled exercise intervention trials that evaluate biomarker changes with different types and doses of physical activities to elucidate further how activity influences breast cancer risk. The ultimate objective of this research is to provide more quantitative data that can be used to enhance the public health recommendations regarding the type, dose, and timing of physical activity required to reduce breast cancer risk.
Dr. Christine Friedenreich is supported by a Health Senior Scholar Award from the Alberta Heritage Foundation for Medical Research. The author wishes to thank Dr. Brigid Lynch and Heather Neilson for their assistance in the writing of this review and Qinggang Wang for the preparation of the figures.
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