The Biological Mechanisms by Which Physical Activity Might Have an Impact on Outcome/Prognosis After a Breast Cancer Diagnosis

  • Melinda L. Irwin


Despite the growing body of observational evidence suggesting a link between PA and breast cancer survival, the mechanisms underlying this relationship are poorly understood. A few small RCTs have examined the impact of exercise on surrogate/biological markers of survival. The beneficial effects of PA may be mediated through a reduction in body fat and beneficial changes in metabolic (e.g., insulin) and sex hormones (e.g., androgens and estrogens), growth factors (IGF-I and associated binding proteins, e.g., IGFBP-3), adipokines (e.g., leptin, adiponectin), and/or inflammation (e.g., CRP). Although much further research is needed to determine the effect of PA on these biological markers, we posit that PA decreases breast cancer death directly and indirectly through multiple, interrelated actions of body fat levels and/or hormonal concentrations and actions. Given the high level of physical inactivity in the population, and the heavy burden that breast cancer creates for the individual and for society, the need for well-designed trials of exercise on breast cancer survival and surrogate/biological markers mediating a potential effect is an urgent public health priority.


Breast Cancer Breast Cancer Survivor Breast Cancer Recurrence Breast Cancer Death Brisk Walking 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    ACS. (2006) Breast Cancer Facts and Figures: 2006–2007. American Cancer Society I, Atlanta.Google Scholar
  2. 2.
    Friedenreich CM. (2001) Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomark Prev 10(4):287–301.Google Scholar
  3. 3.
    Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. (2005) Physical activity and survival after breast cancer diagnosis. J Am Med Assoc 293(20):2479–2486.CrossRefGoogle Scholar
  4. 4.
    Holick CN, Newcomb PA, Trentham-Dietz A, et al. (2008) Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomark Prev 17(2):379–386.CrossRefGoogle Scholar
  5. 5.
    Irwin ML, Smith A, McTiernan A, et al. (2008) Influence of pre- and post-diagnosis physical activity on survival in breast cancer survivors: the health, eating, activity, and lifestyle (HEAL) study. J Clin Oncol 26(24):1–7.CrossRefGoogle Scholar
  6. 6.
    Pierce JP, Stefanick ML, Flatt SW, et al. (2007) Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol 25(17):2345–2351.CrossRefPubMedGoogle Scholar
  7. 7.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. NEJM 348(17):1625–1638.CrossRefPubMedGoogle Scholar
  8. 8.
    Daling JR, Malone KE, Doody DR, Johnson LG, Gralow JR, Porter PL. (2001) Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma. Cancer 92((4)):720–729.CrossRefPubMedGoogle Scholar
  9. 9.
    Kroenke CH, Chen WY, Rosner B, Holmes MD. (2005) Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 23(7):1370–1378.CrossRefPubMedGoogle Scholar
  10. 10.
    Irwin ML, McTiernan A, Baumgartner RN, et al. (2005) Changes in body fat and weight after a breast cancer diagnosis: influence of demographic, prognostic, and lifestyle factors. J Clin Oncol 23(4):774–782.CrossRefPubMedGoogle Scholar
  11. 11.
    Caan BJ, Emond JA, Natarajan L, et al. (2006) Post-diagnosis weight gain and breast cancer recurrence in women with early stage breast cancer. Breast Cancer Res Treat 99(1):47–57.CrossRefPubMedGoogle Scholar
  12. 12.
    Irwin ML, Yasui Y, Ulrich CM, et al. (2003) Effect of exercise on total and intra-abdominal body fat in postmenopausal women: a randomized controlled trial. J Am Med Assoc 289(3):323–330.CrossRefGoogle Scholar
  13. 13.
    Irwin ML, Alvarez-Reeves M, Cadmus L, et al. 2009Randomized controlled trial of exercise on body fat, lean mass, and bone mineral density in breast cancer survivors (Under review)Google Scholar
  14. 14.
    Schmitz KH, Ahmed RL, Hannan PJ, Yee D. (2005) Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins. Cancer Epidemiol Biomark Prev 14(7):1672–1680.CrossRefGoogle Scholar
  15. 15.
    Goodwin PJ, Ennis M, Pritchard KI, et al. (2002) Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20(1):42–51.CrossRefPubMedGoogle Scholar
  16. 16.
    Irwin MLBL, McTiernan A, et al. (2007) Associations between fasting c-peptide and breast cancer death: the Health, Eating, Activity, and Lifestyle (HEAL) Study. AACR Frontiers in Cancer Prevention Meeting, December 2007, Abstract B99.Google Scholar
  17. 17.
    Pollak MNCJ, Shepherd L, et al. (2006) Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. J Clin Oncol 24:(suppl 18S, abstr 524).Google Scholar
  18. 18.
    Gray SG, Stenfeldt Mathiasen I, De Meyts P. (2003) The insulin-like growth factors and insulin-signalling systems: an appealing target for breast cancer therapy?. Horm Metab Res 35((11-12)):857–871.PubMedGoogle Scholar
  19. 19.
    Yu H, Rohan T. (2000) Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92(18):1472–1489.CrossRefPubMedGoogle Scholar
  20. 20.
    Hankinson S, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. (1998) Circulating concentrations of insulin-like growth factor-1 and risk of breast cancer. Lancet 351:1393–1396.CrossRefPubMedGoogle Scholar
  21. 21.
    Goodwin PJ, Ennis M, Pritchard KI, et al. (2002) Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes. Breast Cancer Res Treat 74(1):65–76.CrossRefPubMedGoogle Scholar
  22. 22.
    Ligibel JA, Campbell N, Partridge A, et al. (2008) Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26(6):907–912.CrossRefPubMedGoogle Scholar
  23. 23.
    Irwin ML, Varma K, Cadmus L, et al. (2009) Randomized controlled trial of exercise on insulin and IGFs in breast cancer survivors. Cancer Epidemiol Biomark Prev 18(1):306–313.CrossRefGoogle Scholar
  24. 24.
    Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR. (2003) Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Cancer Epidemiol Biomark Prev 12(8):721–727.Google Scholar
  25. 25.
    Frank LL, Sorensen BE, Yasui Y, et al. (2005) Effects of exercise on metabolic risk variables in overweight postmenopausal women: a randomized clinical trial. Obes Res 13(3):615–.CrossRefPubMedGoogle Scholar
  26. 26.
    Goodyear L. (1998) KBE, glucose transport, and insulin sensitivity. Ann Rev Med 49:235–261.CrossRefPubMedGoogle Scholar
  27. 27.
    Key T, Appleby P, Barnes I, Reeves G. (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616.PubMedGoogle Scholar
  28. 28.
    Howell A, Cuzick J, Baum M, et al. (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365(9453):60–62.CrossRefPubMedGoogle Scholar
  29. 29.
    Thurlimann B, Keshaviah A, Coates AS, et al. (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757.CrossRefPubMedGoogle Scholar
  30. 30.
    McTiernan A, Tworoger SS, Ulrich CM, et al. (2004) Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Res 64(8):2923–2928.CrossRefPubMedGoogle Scholar
  31. 31.
    McTiernan A, Wu L, Chen C, et al. (2006) Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity 14(9):1662–1677.CrossRefPubMedGoogle Scholar
  32. 32.
    McTiernan A, Rajan KB, Tworoger SS, et al. (2003) Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21(10):1961–1966.CrossRefPubMedGoogle Scholar
  33. 33.
    Irwin ML,, Alvarez-Reeves M,, Cadmus L, et al. (2008) RCT of exercise on sex hormones in breast cancer survivors. AACR Frontiers in Cancer Prevention Meeting, December, 2008.Google Scholar
  34. 34.
    Vona-Davis L. (2007) RDA, paracrine, and autocrine factors in breast cancer risk and progression. Endocrine-Related Cancer 14:189–206.CrossRefPubMedGoogle Scholar
  35. 35.
    Jarde T, Caldefie-Chezet F, Damez M, et al. (2008) Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol Rep 19(4):905–911.PubMedGoogle Scholar
  36. 36.
    Housa DHJ, Vernerova Z, Haluzik M. (2006) Adipocytokines and cancer. Physiol Res 55:233–244.PubMedGoogle Scholar
  37. 37.
    Nicolini A, Carpi A, Rossi G. (2006) Cytokines in breast cancer. Cytokine Growth Factor Rev 17:325-337.CrossRefPubMedGoogle Scholar
  38. 38.
    Irwin ML, McTiernan A, Bernstein L, et al. (2005) Relationship of obesity and physical activity with C-peptide, leptin, and insulin-like growth factors in breast cancer survivors. Cancer Epidemiol Biomark Prev 14(12):2881–2888.CrossRefGoogle Scholar
  39. 39.
    Miyoshi YFT, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y, Noguchi S. (2003) Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 9:5699–5704.PubMedGoogle Scholar
  40. 40.
    Arditi JD, Venihaki M, Karalis KP, Chrousos GP. (2007) AnTiproliferative effect of adiponectin on MCF 7 breast cancer cells: a potential hormonal link between obesity and cancer. Horm Metabol Res 39((1)):9-13.CrossRefGoogle Scholar
  41. 41.
    Miyoshi Y, Funahashi T, Kihara S, et al. (2003) Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 9(15):5699–5704.PubMedGoogle Scholar
  42. 42.
    Irwin ML, Alvarez-Reeves M, Cadmus L, et al. (2009) RCT of exercise on leptin and adiponectin in breast cancer survivors. Obesity (Under review).Google Scholar
  43. 43.
    Ardizzoia ALP, Brivio F, et al. (1992) Tumor necrosis factor in sold tumors: increased blood levels in metastatic disease. J Biol Regul Homeost Agents 6:103.PubMedGoogle Scholar
  44. 44.
    Pierce BL, Neuhouser ML, Wener MH, et al. (10 April 2008) Correlates of circulating C-reactive protein and serum amyloid A concentrations in breast cancer survivors. Breast Cancer Res Treat 114:155–167.CrossRefPubMedGoogle Scholar
  45. 45.
    Zhang SM, Lin J, Cook NR, et al. (2007) C-reactive protein and risk of breast cancer. J Natl Cancer Inst 99(11):890–894.CrossRefPubMedGoogle Scholar
  46. 46.
    DeNardo DG, Coussens LM. (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9(4):212.CrossRefPubMedGoogle Scholar
  47. 47.
    McMillan DCEM, Sattar N, Angerson WJ, Johnstone J, McArdle CS. (2001) Measurement of the systematic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer 41((1&2)):64–69.CrossRefPubMedGoogle Scholar
  48. 48.
    Garcia-Tunon IRM, Ruiz A, Fraile B, Paniagua R, Royuela M. (2006) Role of tumor necrosis factor-a and its receptors in human benign breast lesions and tumors (in situ and infiltrative). Cancer Sci 97:1044–1049.CrossRefPubMedGoogle Scholar
  49. 49.
    Knupfer H, Preib R. (2007) Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat 102:129–135.CrossRefPubMedGoogle Scholar
  50. 50.
    Mohamed-Ali VGS, Rawesh A, et al. (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-a in vivo. J Clin Endocrinol Metabol 82:4196–4200.CrossRefGoogle Scholar
  51. 51.
    Fairey AS, Courneya KS, Field CJ, et al. (2005) Effect of exercise training on C-reactive protein in postmenopausal breast cancer survivors: a randomized controlled trial. Brain Behav Immun 19(5):381–388.CrossRefPubMedGoogle Scholar
  52. 52.
    Jones S, Hesselsweet S, Yu H, Irwin ML. (2009) Randomized controlled trial of exercise on inflammation in breast cancer survivors. J Cancer Survivorship (Under review).Google Scholar
  53. 53.
    Fischer CPBA, Perstrup LB, Eskildsen P, Pedersen BK. (2007) Plasma levels of interleukin-6 and c-reactive protein are associated with physical inactivity independent of obesity. Scand J Med Sci Sports 17:580–587.PubMedGoogle Scholar
  54. 54.
    Olson TPDD, Leon AS, Schmitz KH. (2007) Changes in inflammatory biomarkers following one-year of moderate resistance training in overweight women. Int J Obesity 31:996–1003.CrossRefGoogle Scholar
  55. 55.
    Dekker MJLS, Hudson R, et al. (2007) An exercise intervention without weight loss decreases circulating interleukin-6 in lean and obese men with and without type 2 diabetes mellitus. Metabol Clin Exp 56:332–338.Google Scholar
  56. 56.
    Kasapis C, Thompson PD. (2005) The effects of physical activity on serum c-reactive protein and inflammatory markers. J Am College Cardiol 45(10):1563–1569.CrossRefGoogle Scholar
  57. 57.
    Hursting SD, Lashinger LM, Colbert LH, et al. (2007) Energy balance and carcinogenesis: underlying pathways and targets for intervention. Curr Cancer Drug Targets 7(5):484–491.CrossRefPubMedGoogle Scholar
  58. 58.
    Fairey AS, Courneya KS, Field CJ, Mackey JR. (2002) Physical exercise and immune system function in cancer survivors: a comprehensive review and future directions. Cancer 94(2):539–551.CrossRefPubMedGoogle Scholar
  59. 59.
    Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR. (2005) Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors. J Appl Physiol 98(4):1534–1540.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Epidemiology and Public HealthYale School of Public HealthNew HavenUSA

Personalised recommendations