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Journal of Exercise Science & Fitness 10 (2012) 1e7 www.elsevier.com/locate/jesf

Review article

Physical activity and breast cancer risk

Paul D. Loprinzi a,*, Bradley J. Cardinal b, Ellen Smit c, Kerri M. Winters-Stone d
a Department of Exercise Science, Donna & Allan Lansing School of Nursing & Health Sciences, Bellarmine University, Louisville, KY, USA Program in Exercise and Sport Science, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA c Program in Epidemiology, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA d School of Nursing, Oregon Health & Science University, Portland, OR, USA b

Received 26 May 2011; revised 27 July 2011; accepted 7 September 2011 Available online 5 June 2012

Abstract To provide the current evidence linking physical activity to breast cancer risk, the objectives of this review were twofold: (1) to review the epidemiological literature examining the relationship between physical activity and breast cancer risk; and (2) to summarize the mechanisms through which physical activity can inuence risk. A review of the literature was conducted to identify studies that addressed these two objectives. Of the 76 studies reviewed, 40 (53%) reported a protective effect of physical activity on breast cancer risk. The protective effects of physical activity on breast cancer risk are likely to be through changes in sex hormone levels, immune function, adiposity, and insulin-related hormones. To achieve the greatest reduction in risk of breast cancer, regular participation in physical activity should begin in childhood and persist throughout the lifespan. Copyright 2012, The Society of Chinese Scholars on Exercise Physiology and Fitness. Published by Elsevier (Singapore) Pte Ltd. All rights reserved.
Keywords: Epidemiology; Exercise; Survivors; Women

Introduction Except for non-melanoma skin-related cancer, breast cancer is the most common form of cancer among women.1 In 2006, 191,410 women were diagnosed with breast cancer in the USA.1 According to recent estimates, about 12% of women in the general population will develop breast cancer in their lifetime. Some women are inherently at risk for developing breast cancer due to hereditary factors, such as mutations in tumor suppressor genes (e.g., BRCA1 and BRCA2).2 Among women who have inherited a mutation in the BRCA1 or BRCA2 gene, up to 60% will develop breast cancer.2,3 Though comparatively rare, males are also at risk for developing breast cancer, with 2140 new cases reported in 2011.
* Corresponding author. Bellarmine University, Department of Exercise Science, Louisville, KY 40205, USA. Tel.: 1 502 272 8008; fax: 1 502 272 7602. E-mail address: ploprinzi@bellarmine.edu (P.D. Loprinzi).

Fortunately, advances in medical therapy have led to improvements in survival rates among those diagnosed with breast cancer. For example, approximately, 89% of women diagnosed with breast cancer will live at least 5-years post-diagnosis4; however, those surviving up to 20e30 years postdiagnosis are still at a higher risk for breast cancer recurrence than women never diagnosed with cancer.5 Notwithstanding these improvements in breast cancer therapy, new breast cancerghting therapies are costly and are associated with signicant side effects.6,7 Consequently, additional adjuvant therapies that complement traditional systemic therapies are needed. One relatively low-cost, safe, and effective strategy to complement current adjuvant therapies, and possibly aid in the primary prevention of breast cancer, includes the promotion of physical activity. To provide an up-to-date delineation of the relationship between physical activity and breast cancer risk,8 and to discuss candidate mechanisms responsible for this relationship, this manuscript evaluates the current research literature that

1728-869X/$ - see front matter Copyright 2012, The Society of Chinese Scholars on Exercise Physiology and Fitness. Published by Elsevier (Singapore) Pte Ltd. All rights reserved. doi:10.1016/j.jesf.2012.04.004

P.D. Loprinzi et al. / Journal of Exercise Science & Fitness 10 (2012) 1e7
50,54,58e60,63e67,69,71,74e77,79,81e84

investigates the link between physical activity and breast cancer risk, and discusses the mechanisms through which physical activity may reduce cancer risk. The paper concludes by summarizing the implications for health care professionals. Methods An extensive review of the epidemiological literature on the effect of physical activity on breast cancer risk was conducted through PubMed, using the following keywords: physical activity, exercise, and breast cancer. To identify the biological mechanisms thought to inuence the association between physical activity and breast cancer risk, a PubMed search was conducted using the following keywords: exercise, physical activity, breast cancer, and mechanisms. Articles that had these keywords in the title or abstract were obtained and reviewed. The discussion section of related studies were reviewed and manual searches of the reference lists of the articles retrieved were also performed. Only English language manuscripts were included. Level of evidence The effect of physical activity on breast cancer risk was categorized using the following coding scheme: (1) protective effect, if a signicant inverse association was reported; (2) non-signicant inverse association, if a reduction in risk was reported with a non-signicant trend or non-signicant condence interval; (3) no effect, if there was a nonsignicant positive association. Results A total of 76 studies that investigated the association between physical activity and breast cancer risk were identied. Among these, 72 were conducted in women and four in men. Additionally, across these studies, there was considerable variation with regard to the study design, populations, contrast in the exposure variable (i.e., physical activity), and adjustment for confounding variables. The study designs included prospective cohort (n 28),9e36 retrospective cohort (n 5),37e41 and casecontrol (n 43).42e84 Physical activity was assessed during leisure-time,3,9e26,28e31,33e37,39,40,42e47,50,51,53e64,66e74,76e81, 84 transportation,19,38 household,34,38,66,67,76 and in occupational settings.14,15,17,21,24,27,33,35,38,41,48e52,57,63,64,66,67,69, 71,76,78,81e84 All studies measured physical activity either using self-report,9e14,16e40,42,47,50,53,59,60,62,64,66e68,75,78,79,81,82 interview-administered,15,41,43e46,51,54e58,61,63,69e73,76,80,83,84 or telephone-administered methods,48,49,74,77 with no studies using an objective-measure of physical activity and few studies using reliable and/or valid subjective measures of physical activity.12,16,18,21,22,30,51,54,66e68 Despite the great variability in study characteristics, results generally supported a positive link between physical activity and breast cancer risk. Of the 76 studies reviewed, 40 (53%) reported a statistically signicant protective effect for physical activity on breast cancer risk10,13,14,16,21,22,30,33e36,38,40e45,

; 28 (37%) studies found a non-signicant risk reduction of physical activity on reducing breast cancer risk9,11,17e19,23e27,31,32,37,39,47e49,51,53,55,57,61,62, 70,72,73,78 ; and only eight (10%) studies had no evidence for an association between physical activity and breast cancer risk.12,15,20,29,52,56,68,80 Notably, none of the studies reviewed observed a signicant positive (i.e., harmful) association between physical activity and breast cancer risk. Of the 40 studies demonstrating a reduction in breast cancer risk, the magnitude of the decrease was, on average, 36%, with case-control studies (40%) more frequently observing a reduction in breast cancer risk compared to cohort studies (31%). When all the studies were included, the magnitude of decrease was 29%, with again, case control studies (35%) reporting a greater reduction in breast cancer risk than cohort studies (21%) (Figs. 1 and 2). To evaluate whether specic aspects of physical activity participation inuence breast cancer risk, studies have examined the effect of timing (i.e., current or historic/past activity behavior) and intensity, including, moderate-intensity13,20e23,34,54,55,63,67,83 and vigorous intensity13,17,18,20e23,28,29,31,34,42,47,51,54,55,58,63,67, 72,76,83 exercise on reductions in breast cancer risk. To investigate the inuence of the timing of physical activity on breast cancer risk, studies have assessed activity behavior in different periods of the lifespan, such as adolescence,18,20e22,42,47,50,51, 54,56,62,66,68,69e72,74,75,77e80,83 young adulthood,14,18,21,29,42,54,56, 66,68,75,76,78,79 18,20e22,26,42,50,54,66,68,69,76,83 middle-age, and lateadulthood,18,22,38,42,50,54,66,68,69,76 as well as different timeintervals prior to breast cancer diagnosis, such as one to two years prior,13,29,47,51,56,59,70,75,83 10-years prior,10,46,51,53,71 20years prior,51 and an average of these time-periods (i.e., lifetime activity behavior).13,16,28,43,45,46,51,54,63,66e68,71,76,83,84 When compared, the effect of physical activity on reducing breast cancer was stronger for vigorous-intensity physical activity (26%) than moderate-intensity physical activity (13%), and assessment of lifetime physical activity (30%) was more consistently associated with reduced breast cancer risk, compared to regular participation in physical activity during adolescence (26%), young-adulthood (11%), middle-age years (12%), and late-adulthood (23%). Studies have also examined potential effect modiers on the association between physical activity and breast cancer risk. The most common effect modiers included menopausal status,9,10,17,19,30,31,33,35,42,43,49e51,54e56,58e60,62,63,66,67,71,73,79,81,84 body mass index,9,10,12e14,19,21e24,26,30,31,33e35,49,50,56,59,75,76,

Fig. 1. Strength of association between physical activity and breast cancer risk among cohort studies.

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metabolic hormones (leptin and adiponectin); reductions in markers of insulin resistance (i.e., insulin, glucose, C-peptide, and glycosylated hemoglobin); and reduced inammatory markers [i.e., tumor necrosis factor alpha, interleukin-6 (IL-6), and C-reactive protein].88e91 Sex hormones and adiposity It is well-established that women with increased exposure to sex hormones, namely estrogen and progesterone, are at an increased risk for breast cancer.92,93 Elevated levels of sex hormones and cumulative exposure to sex hormones stimulates tumor development and growth through mammary cell proliferation.94 Consequently, women with an early onset of menarche, regular lifetime ovulatory cycles, and late menopause are at an elevated risk for breast cancer,95 with an increased risk ranging from 20% to over 400%.96e100 Participation in regular physical activity might reduce circulating levels of sex hormones, and thus reduce breast cancer risk, by delaying the onset of menarche in childhood, and in adulthood, inducing menstrual cycle irregularities, such as anovulation, oligomenorrhoea and amenorrhea. This assertion is supported by both observational studies,101e103 and exercise intervention studies.104,105 Importantly, in addition to the direct inuence of physical activity, it is likely that delaying the onset of menarche and inducing anovulation is inuenced by levels of adiposity. Adipose cells act as a secondary hormonal gland by secreting estrone and estradiol; thus, reduced circulating levels of sex hormones might require both prolonged exercise and caloric restriction to minimize adipose cell hypertrophy and proliferation. Future research is needed to determine if physical activity can affect sex hormones independent of changes in adiposity. Immune function Chronic inammation has been recognized as a risk factor for cancer,106 particularly through cellular changes and oxidative stress associated with inammation.107 At moderate levels and intensities, regular participation in physical activity might help reduce inammation by decreasing proliferation of immunological products, such as C-reactive protein, interleukin-6, macrophages, natural killer cells, lymphokineactivated killer cells, and lymphocytes.90,108 A randomized controlled trial in obese non-cancer postmenopausal women showed that a 6-month weight loss program, comprised of regular exercise and a hypocaloric diet, signicantly decreased levels of interleukin-6, C-reactive protein, and tumor necrosis factor-alpha.109 In contrast, there were no changes in these immunological biomarkers in the diet-only control group. Additional research is warranted as to whether physical activity can reduce inammation in women with breast cancer. Insulin-related factors Long-term exposure to elevated levels of insulin has also been associated with breast cancer risk,110 as well as a two and

Fig. 2. Strength of association between physical activity and breast cancer risk among case-control studies.

family history of breast cancer,13,23,45,46,59,76,83 and parity.13,21,23,34,44,49,50,59,74,75,83 When compared, the effect of physical activity on reducing breast cancer was stronger for postmenopausal women (30%) than premenopausal women (26%); participants not overweight (37%) compared to overweight participants (19%); women without a history of breast cancer (21%) compared to women with a family history of breast cancer (12%); and little difference was found between parous women (23%) and nulliparous women (25%). Discussion Collectively, the epidemiologic literature provides substantial evidence that regular participation in physical activity can reduce the risk of breast cancer. To aid in the prevention of breast cancer, regular participation in physical activity should begin in early childhood, persist throughout adulthood, and be of at least moderate-intensity. While it might be concluded that the data are conclusive, the lesson learned regarding the use of hormone replacement therapy suggests caution. Hormone replacement therapy was considered, by many, to decrease convincingly the risk of heart disease and cognitive function loss based on epidemiologic data, only to be shown to be associated with increased risks of heart disease and cognitive dysfunction from the results of placebo-controlled, double-blind, randomized clinical trials.85,86 Understanding the causal pathway between physical activity and breast cancer risk could be helpful in the development of physical activity interventions by providing further information on the dose, intensity, and frequency of physical activity across various exercise domains needed to protect against cancer. Establishing the biological mechanisms that underlie an association between physical activity and breast cancer risk is an important next step in developing a body of evidence linking health behavior to disease outcomes. The proposed mechanisms by which physical activity exerts a protective effect against cancer can be broadly divided into the following categories: (1) decreases in sex hormones; (2) decreases in adiposity; (3) increases in immune function; and (4) changes in markers of insulin resistance.87 Some studies support the concept that physical activity reduces breast cancer risk through favorable changes in the following biological mechanisms/biomarkers: decreased adiposity; decreased available sex hormones (i.e., lower estrogens and androgens); higher sex hormone binding globulin (SHBG) levels; decreased

83,84

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three times higher risk for breast cancer recurrence and breast cancer death, respectively.111 Specically, high insulin levels stimulate the production of insulin-like growth factors (IGFs), which are associated with increased breast cancer risk through their stimulatory effect on cell turnover.112 In addition to specic biomarkers (e.g., IGFs), insulin-resistance is thought to play an important role in breast cancer development. For example, in a meta-analysis conducted by Larsson and colleagues113 a 20% increased breast cancer risk among individuals with type-2 diabetes was found, though not all studies have shown such an association.114 Regular participation in physical activity is positively associated with insulin sensitivity115 and inversely associated with fasting insulin levels116 and IGFs.117 The physical activity-lowering effect on IGFs might not only inhibit mammary cell turnover, but decreased IGFs might also reduce the availability of sex hormones through hepatic synthesis of sex hormone binding globulin.118 Other potential factors In addition to the potential mechanisms previously discussed, there are other possible mechanisms that might mediate the relationship between physical activity and breast cancer risk. It is conceivable that physical activity could inuence breast cancer risk indirectly through behavioral practices such as cancer screening; therefore, future studies investigating the biological mechanisms responsible for the protective effect of exercise on breast cancer should control for such behavioral practices, as it is possible that physically active, health conscious individuals are likely to employ other practices, such as cancer screening (e.g., mammography), to help prevent cancer development. Conclusion Overall, there is substantial evidence that regular participation in physical activity can reduce the risk of breast cancer. The mechanisms responsible for the protective effect of physical activity on breast cancer risk and recurrence are likely to be through changes in sex hormone levels, immune function, adiposity, and insulin-related factors. The epidemiological evidence suggests that to aid in the prevention of breast cancer, regular participation in physical activity should begin in early childhood, persist throughout adulthood, and be of at least moderate-intensity. As recommended by Irwin et al119 and consistent with current physical activity guidelines,120 children and adolescents (6e17 years e both boys and girls) should engage in at least 1 hour of moderateintensity aerobic activity on a daily basis and perform vigorous-intensity aerobic activity at least 3 days a week. Additionally, children and adolescents should participate in muscle and bone strengthening activities at least 3 days a week. Although it is unknown how much exercise is needed for maximum reduction in breast cancer risk, a reasonable approach would be to follow the physical activity guidelines for all adults. Thus, adult men and women should engage in at least 150 minutes of moderate-intensity and/or at least 75

minutes of vigorous-intensity physical activity per week. Additionally, adults should participate in muscle and bone strengthening at least 2 days a week. Implications for health care professionals The convincing evidence for physical activity reducing breast cancer risk suggests that health care professionals should encourage their patients to engage in physical activity on a regular basis. To enhance the patients condence and motivation to engage in physical activity, health care professionals, whenever possible, should use evidence-based patient counseling techniques such as Brief Negotiation Interviewing and Motivational Interviewing.121e123 By adopting these patientcentered approaches, health care professionals are more likely to dialogue with their patients about their physical activity behavior. Notably, brief motivational interviewing by health care professionals has been shown to be a feasible and potentially effective ofce-based strategy for promoting physical activity in children and adults.124 References
1. US Cancer Statistics Working Group. United States Cancer Statistics: 1999e2006 Incidence and Mortality Web-based Report. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute. Available from: http://cdc. gov/uscs; December 2010. 2. Kadouri L, Hubert A, Rotenberg Y, et al. Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. J Med Genet. 2007;44:467e471. 3. PDQ Cancer Information Summary. Genetics of Breast and Ovarian Cancer 2012. Bethesda, MD: National Cancer Institute. Available from: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/health professional; December 2010. 4. Ries LAG, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Horner MJ, Howlader N, Eisner MP, Reichman M, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD. Available from: http://seer.cancer.gov/csr/1975_ 2004/, based on November 2006 SEER data submission, posted to the SEER web site, 2007. 5. Dixon JM, Montgomery D. Follow-up after breast cancer. BMJ. 2008;336:107e108. 6. Burstein HJ, Griggs JJ. Adjuvant hormonal therapy for early-stage breast cancer. Surg Oncol Clin N Am. 2010;19:639e647. 7. Will BP, Berthelot JM, Le Petit C, et al. Estimates of the lifetime costs of breast cancer treatment in Canada. Eur J Cancer. 2000;36:724e735. 8. Monninkhof EM, Elias SG, Vlems FA, et al. Physical activity and breast cancer: a systematic review. Epidemiology. 2007;18:137e157. 9. Albanes D, Blair A, Taylor PR. Physical activity and risk of cancer in the NHANES I population. Am J Public Health. 1989;79(6):744e750. 10. Berslow RA, Ballard-Barbash R, Munoz K, et al. Long-term recreational physical activity and breast cancer in the National Health and Nutrition Examination Survey I epidemiologic follow-up study. Cancer Epidemiol Biomarkers Prev. 2001;10:805e808. 11. Cerhan JR, Chiu BC, Wallace RB, et al. Physical activity, physical function, and the risk of breast cancer in a prospective study among elderly women. J Gerontol A Biol Sci Med Sci. 1998;53:M251eM256. 12. Colditz GA, Feskanich D, Chen WY, et al. Physical activity and risk of breast cancer in premenopausal women. Br J Cancer. 2003;89:847e851. 13. Dallal CM, Sullivan-Halley J, Ross RK, et al. Long-term recreational physical activity and risk of invasive and in situ breast cancer: the California teachers study. Arch Intern Med. 2007;167:408e415.

P.D. Loprinzi et al. / Journal of Exercise Science & Fitness 10 (2012) 1e7 14. Dirx MJ, Voorrips LE, Goldbohm RA, et al. Baseline recreational physical activity, history of sports participation, and postmenopausal breast carcinoma risk in the Netherlands Cohort Study. Cancer. 2001;92:1638e1649. 15. Dorgan JF, Brown C, Barrett M, et al. Physical activity and risk of breast cancer in the Framingham Heart Study. Am J Epidemiol. 1994;139:662e669. 16. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758e1764. 17. Howard RA, Leitzmann MF, Linet MS, et al. Physical activity and breast cancer risk among pre- and postmenopausal women in the U.S. Radiologic Technologists cohort. Cancer Causes Control. 2009;20:323e333. 18. Lee IM, Rexrode KM, Cook NR, et al. Physical activity and breast cancer risk: the Womens Health Study (United States). Cancer Causes Control. 2001;12:137e145. 19. Luoto R, Latikka P, Pukkala E, et al. The effect of physical activity on breast cancer risk: a cohort study of 30,548 women. Eur J Epidemiol. 2000;16:973e980. 20. Margolis KL, Mucci L, Braaten T, et al. Physical activity in different periods of life and the risk of breast cancer: the Norwegian-Swedish Womens Lifestyle and Health cohort study. Cancer Epidemiol Biomarkers Prev. 2005;14:27e32. 21. Maruti SS, Willett WC, Feskanich D, et al. A prospective study of agespecic physical activity and premenopausal breast cancer. J Natl Cancer Inst. 2008;100:728e737. 22. McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Womens Health Initiative Cohort Study. JAMA. 2003;290:1331e1336. 23. Moore DB, Folsom AR, Mink PJ, et al. Physical activity and incidence of postmenopausal breast cancer. Epidemiology. 2000;11:292e296. 24. Moradi T, Adami HO, Ekbom A, et al. Physical activity and risk for breast cancer a prospective cohort study among Swedish twins. Int J Cancer. 2002;100:76e81. 25. Paffenbarger RS Jr, Lee IM, Wing AL. The inuence of physical activity on the incidence of site-specic cancers in college alumni. Adv Exp Med Biol. 1992;322:7e15. 26. Patel AV, Callel EE, Bernstein L, et al. Recreational physical activity and risk of postmenopausal breast cancer in a large cohort of US women. Cancer Causes Control. 2003;14:519e529. 27. Pukkala E, Poskiparta M, Apter D, et al. Life-long physical activity and cancer risk among Finnish female teachers. Eur J Cancer Prev. 1993;2:369e376. 28. Rockhill B, Willett WC, Hunter DJ, et al. A prospective study of recreational physical activity and breast cancer risk. Arch Intern Med. 1999;159:2290e2296. 29. Rockhill B, Willett WC, Hunter DJ, et al. Physical activity and breast cancer risk in a cohort of young women. J Natl Cancer Inst. 1998;90:1155e1160. 30. Sesso HD, Paffenbarger RS Jr, Lee IM. Physical activity and breast cancer risk in the College Alumni Health Study (United States). Cancer Causes Control. 1998;9:433e439. 31. Silvera SA, Jain M, Howe GR, et al. Energy balance and breast cancer risk: a prospective cohort study. Breast Cancer Res Treat. 2006;97:97e106. 32. Steenland K, Nowlin S, Palu S. Cancer incidence in the National Health and Nutrition Survey I. Follow-up data: diabetes, cholesterol, pulse and physical activity. Cancer Epidemiol Biomarkers Prev. 1995;4:807e811. 33. Suzuki S, Kojima M, Tokudome S, et al. Effect of physical activity on breast cancer risk: ndings of the Japan collaborative cohort study. Cancer Epidemiol Biomarkers Prev. 2008;17:3396e3401. 34. Tehard B, Friedenreich CM, Oppert JM, et al. Effect of physical activity on women at increased risk of breast cancer: results from the E3N cohort study. Cancer Epidemiol Biomarkers Prev. 2006;15:57e64. 35. Thune I, Brenn T, Lund E, et al. Physical activity and the risk of breast cancer. N Engl J Med. 1997;336:1269e1275. 36. Wyrwich KW, Wolinsky FD. Physical activity, disability, and the risk of hospitalization for breast cancer among older women. J Gerontol A Biol Sci Med Sci. 2000;55:M418eM421. 37. Frisch RE, Wyshak G, Albright NL, et al. Lower prevalence of breast cancer and cancers of the reproductive system among former college athletes compared to non-athletes. Br J Cancer. 1985;52:885e891.

38. George SM, Irwin ML, Matthews CE, et al. Beyond recreational physical activity: examining occupational and household activity, transportation activity, and sedentary behavior in relation to postmenopausal breast cancer risk. Am J Public Health. 2010;100:2288e2295. 39. Pijpe A, Manders P, Brohet RM, et al. Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers. Breast Cancer Res Treat. 2010;120:235e244. 40. Wyshak G, Frisch RE. Breast cancer among former college athletes compared to non-athletes: a 15-year follow-up. Br J Cancer. 2000;82:726e730. 41. Zheng W, Shu XO, McLaughlin JK, et al. Occupational physical activity and the incidence of cancer of the breast, corpus uteri, and ovary in Shanghai. Cancer. 1993;71:3620e3624. 42. Adams-Campbell LL, Rosenberg L, Rao RS, et al. Strenuous physical activity and breast cancer risk in African-American women. J Natl Med Assoc. 2001;93:267e275. 43. Awatef M, Olfa G, Rim C, et al. Physical activity reduces the risk of breast cancer: a case-controlstudy in Tunisian population. Cancer Epidemiol. 2011;35:540e544. 44. Bernstein L, Henderson BE, Hanisch R, et al. Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst. 1994;86:1403e1408. 45. Bernstein L, Patel AV, Ursin G, et al. Lifetime recreational exercise activity and breast cancer risk among black women and white women. J Natl Cancer Inst. 2005;97:1671e1679. 46. Carpenter CL, Ross RK, Paganini-Hill A, et al. Effect of family history, obesity and exercise on breast cancer risk among postmenopausal women. Int J Cancer. 2003;106:96e102. 47. Chen CL, White E, Malone KE, et al. Leisure-time physical activity in relation to breast cancer among young women (Washington, United States). Cancer Causes Control. 1997;8:77e84. 48. Coogan PF, Aschengrau A. Occupational physical activity and breast cancer risk in the upper Cape Cod cancer incidence study. Am J Ind Med. 1999;36:279e285. 49. Coogan PF, Newcomb PA, Clapp RW, et al. Physical activity in usual occupation and risk of breast cancer (United States). Cancer Causes Control. 1997;8:626e631. 50. DAvanzo B, Nanni O, La Vecchia C, et al. Physical activity and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996;5:155e160. 51. Dorn J, Vena J, Brasure J, et al. Lifetime physical activity and breast cancer risk in pre- and postmenopausal women. Med Sci Sports Exerc. 2003;35:278e285. 52. Dosemeci M, Hayes RB, Vetter R, et al. Occupational physical activity, socioeconomic status, and risks of 15 cancer sites in Turkey. Cancer Causes Control. 1993;4:313e321. 53. Ewertz M, Holmberg L, Tretli S, et al. Risk factors for male breast cancer e a case-control study from Scandinavia. Acta Oncol. 2001;40: 467e471. 54. Friedenreich CM, Bryant HE, Courneya KS. Case-control study of lifetime physical activity and breast cancer risk. Am J Epidemiol. 2001;154:336e347. 55. Friedenreich CM, Rohan TE. Physical activity and risk of breast cancer. Eur J Cancer Prev. 1995;4:145e151. 56. Gammon MD, Schoenberg JB, Britton JA, et al. Recreational physical activity and breast cancer risk among women under age 45 years. Am J Epidemiol. 1998;147:273e280. 57. Gao CM, Tajima K, Ding JH, et al. Body size, physical activity and risk of breast cancer e a case control study in Jangsu Province of China. Asian Pac J Cancer Prev. 2009;10:877e881. 58. Gilliland FD, Li YF, Baumgartner K, et al. Physical activity and breast cancer risk in hispanic and non-hispanic white women. Am J Epidemiol. 2001;154:442e450. 59. Hirose K, Hamajima N, Takezaki T, et al. Physical exercise reduces risk of breast cancer in Japanese women. Cancer Sci. 2003;94:193e199. 60. Hirose K, Tajima K, Hamajima N, et al. A large-scale, hospital-based case-control study of risk factors of breast cancer according to menopausal status. Jpn J Cancer Res. 1995;86:146e154. 61. Hsing AW, McLaughlin JK, Cocco P, et al. Risk factors for male breast cancer (United States). Cancer Causes Control. 1998;9:269e275.

P.D. Loprinzi et al. / Journal of Exercise Science & Fitness 10 (2012) 1e7 87. Friedenreich CM, Cust AE. Physical activity and breast cancer risk: impact of timing, type and dose of activity and population subgroup effects. Br J Sports Med. 2008;42:636e647. 88. Campbell KL, McTiernan A. Exercise and biomarkers for cancer prevention studies. J Nutr. 2007;137(1 Suppl.):161Se169S. 89. McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer. 2008;8:205e211. 90. Neilson HK, Friedenreich CM, Brockton NT, et al. Physical activity and postmenopausal breast cancer: proposed biologic mechanisms and areas for future research. Cancer Epidemiol Biomarkers Prev. 2009;18:11e27. 91. Rose DP, Komninou D, Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev. 2004;5:153e165. 92. Doisneau-Sixou SF, Sergio CM, Carroll JS, et al. Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr Relat Cancer. 2003;10:179e186. 93. Pike MC, Spicer DV, Dahmoush L, et al. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev. 1993;15:17e35. 94. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270e282. 95. Henderson BE, Ross RK, Judd HL. Do regular ovulatory cycles increase breast cancer risk? Cancer. 1985;56:1206e1208. 96. Berrino F, Muti P, Micheli A, et al. Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst. 1996;88:291e296. 97. Dorgan JF, Longcope C, Stephenson HE Jr, et al. Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996;5:533e539. 98. Thomas HV, Key TJ, Allen DS, et al. A prospective study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey. Br J Cancer. 1997;75:1075e1079. 99. Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, et al. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst. 1995;87:190e197. 100. Wysowski DK, Comstock GW, Helsing KJ, et al. Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol. 1987;125:791e799. 101. Bernstein L, Ross RK, Lobo RA, et al. The effects of moderate physical activity on menstrual cycle patterns in adolescence: implications for breast cancer prevention. Br J Cancer. 1987;55:681e685. 102. Frisch RE, Gotz-Welbergen AV, McArthur JW, et al. Delayed menarche and amenorrhea of college athletes in relation to age of onset of training. JAMA. 1981;246:1559e1563. 103. Frisch RE, Wyshak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med. 1980;303:17e19. 104. Bonen A, Ling WY, MacIntyre KP, et al. Effects of exercise on the serum concentrations of FSH, LH, progesterone, and estradiol. Eur J Appl Physiol Occup Physiol. 1979;42:15e23. 105. Bullen BA, Skrinar GS, Beitins IZ, et al. Induction of menstrual disorders by strenuous exercise in untrained women. N Engl J Med. 1985;312:1349e1353. 106. Aggarwal BB, Shishodia S, Sandur SK, et al. Inammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72:1605e1621. 107. Coussens LM, Werb Z. Inammation and cancer. Nature. 2002;420:860e867. 108. Irwin ML. Randomized controlled trials of physical activity and breast cancer prevention. Exerc Sport Sci Rev. 2006;34:182e193. 109. You T, Berman DM, Ryan AS, et al. Effects of hypocaloric diet and exercise training on inammation and adipocyte lipolysis in obese postmenopausal women. J Clin Endocrinol Metab. 2004;89:1739e1746. 110. Kaaks R. Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control. 1996;7:605e625. 111. Goodwin PJ, Ennis M, Pritchard KI, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol. 2002;20:42e51. 112. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351:1393e1396. 113. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121:856e862.

62. Hu YH, Nagata C, Shimizu H, et al. Association of body mass index, physical activity, and reproductive histories with breast cancer: a casecontrol study in Gifu, Japan. Breast Cancer Res Treat. 1997;43:65e72. 63. John EM, Horn-Ross PL, Koo J. Lifetime physical activity and breast cancer risk in a multiethnic population: the San Francisco Bay area breast cancer study. Cancer Epidemiol Biomarkers Prev. 2003;12:1143e1152. 64. Johnson KC, Pan S, Mao Y. Risk factors for male breast cancer in Canada, 1994e1998. Eur J Cancer Prev. 2002;11:253e263. 65. Kamarudin R, Shah SA, Hidayah N. Lifestyle factors and breast cancer: a case-control study in Kuala Lumpur, Malaysia. Asian Pac J Cancer Prev. 2006;7:51e54. 66. Kruk J. Lifetime physical activity and the risk of breast cancer: a casecontrol study. Cancer Detect Prev. 2007;31:18e28. 67. Kruk J. Intensity of lifetime physical activity and breast cancer risk among Polish women. J Sports Sci. 2009;27:437e445. 68. Lee IM, Cook NR, Rexrode KM, et al. Lifetime physical activity and risk of breast cancer. Br J Cancer. 2001;85:962e965. 69. Levi F, Pasche C, Lucchini F, et al. Occupational and leisure time physical activity and the risk of breast cancer. Eur J Cancer. 1999;35:775e778. 70. Marcus PM, Newman B, Moorman PG, et al. Physical activity at age 12 and adult breast cancer risk (United States). Cancer Causes Control. 1999;10:293e302. 71. Matthews CE, Shu XO, Jin F, et al. Lifetime physical activity and breast cancer risk in the Shanghai Breast Cancer Study. Br J Cancer. 2001;84:994e1001. 72. McTiernan A, Stanford JL, Weiss NS, et al. Occurrence of breast cancer in relation to recreational exercise in women age 50e64 years. Epidemiology. 1996;7:598e604. 73. Mezzetti M, La Vecchia C, Decarli A, et al. Population attributable risk for breast cancer: diet, nutrition, and physical exercise. J Natl Cancer Inst. 1998;90:389e394. 74. Mittendorf R, Longnecker MP, Newcomb PA, et al. Strenuous physical activity in young adulthood and risk of breast cancer (United States). Cancer Causes Control. 1995;6:347e353. 75. Moradi T, Nyren O, Zack M, et al. Breast cancer risk and lifetime leisure-time and occupational physical activity (Sweden). Cancer Causes Control. 2000;11:523e531. 76. Peplonska B, Lissowska J, Hartman TJ, et al. Adulthood lifetime physical activity and breast cancer. Epidemiology. 2008;19:226e236. 77. Shoff SM, Newcomb PA, Trentham-Dietz A, et al. Early-life physical activity and postmenopausal breast cancer: effect of body size and weight change. Cancer Epidemiol Biomarkers Prev. 2000;9:591e595. 78. Steindorf K, Schmidt M, Kropp S, et al. Case-control study of physical activity and breast cancer risk among premenopausal women in Germany. Am J Epidemiol. 2003;157:121e130. 79. Suzuki R, Iwasaki M, Kasuga Y, et al. Leisure-time physical activity and breast cancer risk by hormone receptor status: effective life periods and exercise intensity. Cancer Causes Control. 2010;21:1787e1798. 80. Taioli E, Barone J, Wynder EL. A case-control study on breast cancer and body mass. The American Health Foundation - Division of Epidemiology. Eur J Cancer. 1995;31A:723e728. 81. Ueji M, Ueno E, Osei-Hyiaman D, et al. Physical activity and the risk of breast cancer: a case-control study of Japanese women. J Epidemiol. 1998;8:116e122. 82. Vena JE, Graham S, Zielezny M, et al. Occupational exercise and risk of cancer. Am J Clin Nutr. 1987;45(1 Suppl.):318e327. 83. Verloop J, Rookus MA, van der Kooy K, et al. Physical activity and breast cancer risk in women aged 20e54 years. J Natl Cancer Inst. 2000;92:128e135. 84. Yang D, Bernstein L, Wu AH. Physical activity and breast cancer risk among Asian-American women in Los Angeles: a case-control study. Cancer. 2003;97:2565e2575. 85. Beral V, Banks E, Reeves G. Evidence from randomised trials on the longterm effects of hormone replacement therapy. Lancet. 2002;360:942e944. 86. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Womens Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2663e2672.

P.D. Loprinzi et al. / Journal of Exercise Science & Fitness 10 (2012) 1e7 114. Mink PJ, Shahar E, Rosamond WD, et al. Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study. Am J Epidemiol. 2002;156:349e352. 115. Borghouts LB, Keizer HA. Exercise and insulin sensitivity: a review. Int J Sports Med. 2000;21:1e12. 116. Irwin ML, Mayer-Davis EJ, Addy CL, et al. Moderate-intensity physical activity and fasting insulin levels in women: the Cross-Cultural Activity Participation Study. Diabetes Care. 2000;23:449e454. 117. Allen NE, Appleby PN, Kaaks R, et al. Lifestyle determinants of serum insulin-like growth-factor-I (IGF-I), C-peptide and hormone binding protein levels in British women. Cancer Causes Control. 2003;14: 65e74. 118. Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc. 2001;60: 91e106.

119. Irwin ML, George SM, Matthews CE. Physical activity and breast cancer: prevention, survival, and mechanisms. Research Digest. 2010;11:1e9. 120. U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for Americans. Available from: http://www.health.gov/ paguidelines/; October 2008. 121. Cardinal BJ, Levy SS, John DH, et al. Counseling patients for physical activity. Am J Med Sport. 2002;4:364e371. 122. Miller WR, Rollnick S. Motivational Interviewing: Preparing People for Change. 2nd ed. New York, NY: Guilford Press; 2002. 123. Pinto BM, Goldstein MG, Marcus BH. Activity counseling by primary care physicians. Prev Med. 1998;27:506e513. 124. Hardcastle S, Taylor A, Bailey M, et al. A randomised controlled trial on the effectiveness of a primary health care based counselling intervention on physical activity, diet and CHD risk factors. Patient Educ Couns. 2008;70:31e39.