Breast Cancer Research and Treatment

, Volume 113, Issue 3, pp 567–576 | Cite as

The influence of overweight and insulin resistance on breast cancer risk and tumour stage at diagnosis: a prospective study

  • Anne E. Cust
  • Tanja StocksEmail author
  • Annekatrin Lukanova
  • Eva Lundin
  • Göran Hallmans
  • Rudolf Kaaks
  • Håkan Jonsson
  • Pär Stattin


It is hypothesized that insulin resistance and related metabolic factors may influence breast cancer risk, however the epidemiological evidence remains inconclusive. We conducted a case–control study nested in a prospective cohort in Northern Sweden, to clarify the associations of body mass index (BMI), leptin, adiponectin, C-peptide, and glycated haemoglobin (HbA1c) with breast cancer risk. We also investigated whether these associations may be modified by age at diagnosis, tumour stage, and oestrogen and progesterone receptor status. During follow-up, 561 women developed invasive breast cancer and 561 matched controls were selected. Conditional logistic regression was used to calculate odds ratios (OR) as estimates of relative risk, and 95% confidence intervals (CI). The associations of BMI, leptin and HbA1c with breast cancer risk differed significantly according to whether the tumour was diagnosed as stage I or stage II–IV (P heterogeneity all <0.05). These factors were significantly inversely associated with risk in the group of stage I tumours, with ORs for top vs. bottom tertile for BMI of 0.48 (95% CI, 0.30–0.78, P trend = 0.004); leptin, 0.64 (95% CI, 0.41–1.00, P trend = 0.06); and HbA1c, 0.47 (95% CI, 0.28–0.80, P trend = 0.005). For stage II–IV tumours, there was a suggestion of an increased risk with higher levels of these factors. There were no significant differences in the associations of BMI, leptin, adiponectin, C-peptide and HbA1c with breast cancer risk in subgroups of age at diagnosis or tumour receptor status. This prospective study suggests that BMI, leptin and HbA1c influence breast tumour initiation and progression.


Adiponectin Breast cancer C-peptide Glycated haemoglobin Leptin Obesity Overweight 



We thank Åsa Ågren, project database manager at the Medical Biobank, Umeå University Hospital, Sweden, for co-ordinating data, Sara Nilsson and Sören Holmgren, database executing officers at the Medical Biobank, Umeå University Hospital, Sweden, for managing and completing the study file, and Karin Hjertkvist, laboratory assistant at the Department of Medical Biosciences, Clinical Chemistry, Umeå University, for analysing plasma hormone levels. This study was funded by the World Cancer Research Fund, International Grant 2002/30, the Swedish Cancer Society 04–0417, and by the Västerbotten County Council. Anne Cust was supported by a PhD scholarship from the University of Sydney and a Research Scholar Award from the Cancer Institute NSW, Australia.


  1. 1.
    van den Brandt PA, Spiegelman D, Yaun SS et al (2000) Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 152:514–527PubMedCrossRefGoogle Scholar
  2. 2.
    MacInnis RJ, English DR, Gertig DM et al (2004) Body size and composition and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 13:2117–2125PubMedGoogle Scholar
  3. 3.
    Rosenberg LU, Einarsdottir K, Friman EI et al (2006) Risk factors for hormone receptor-defined breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 15:2482–2488PubMedCrossRefGoogle Scholar
  4. 4.
    Carmichael AR (2006) Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 113:1160–1166PubMedCrossRefGoogle Scholar
  5. 5.
    Alberti KG, Zimmet P, Shaw J (2006) Metabolic syndrome-a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23:469–480PubMedCrossRefGoogle Scholar
  6. 6.
    Weinehall L, Hallgren CG, Westman G et al (1998) Reduction of selection bias in primary prevention of cardiovascular disease through involvement of primary health care. Scand J Prim Health Care 16:171–176PubMedCrossRefGoogle Scholar
  7. 7.
    Stocks T, Lukanova A, Rinaldi S et al (2007) Insulin resistance is inversely related to prostate cancer: A prospective study in Northern Sweden. Int J Cancer 120:2678–2686PubMedCrossRefGoogle Scholar
  8. 8.
    Calle EE, Rodriguez C, Walker-Thurmond K et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638PubMedCrossRefGoogle Scholar
  9. 9.
    Wolf I, Sadetzki S, Gluck I et al (2006) Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. Eur J Cancer 42:1077–1082PubMedCrossRefGoogle Scholar
  10. 10.
    Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13:279–292PubMedCrossRefGoogle Scholar
  11. 11.
    Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5:153–165PubMedCrossRefGoogle Scholar
  12. 12.
    Rose DP, Gilhooly EM, Nixon DW (2002) Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Int J Oncol 21:1285–1292PubMedGoogle Scholar
  13. 13.
    Vona-Davis L, Rose DP (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14:189–206PubMedCrossRefGoogle Scholar
  14. 14.
    Bruning PF, Bonfrer JM, van Noord PA et al (1992) Insulin resistance and breast-cancer risk. Int J Cancer 52:511–516PubMedCrossRefGoogle Scholar
  15. 15.
    Yang G, Lu G, Jin F et al (2001) Population-based, case-control study of blood C-peptide level and breast cancer risk. Cancer Epidemiol Biomarkers Prev 10:1207–1211PubMedGoogle Scholar
  16. 16.
    Del Giudice ME, Fantus IG, Ezzat S et al (1998) Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 47:111–120PubMedCrossRefGoogle Scholar
  17. 17.
    Schairer C, Hill D, Sturgeon SR et al (2004) Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women. Int J Cancer 108:773–779PubMedCrossRefGoogle Scholar
  18. 18.
    Malin A, Dai Q, Yu H et al (2004) Evaluation of the synergistic effect of insulin resistance and insulin-like growth factors on the risk of breast carcinoma. Cancer 100:694–700PubMedCrossRefGoogle Scholar
  19. 19.
    Jernstrom H, Barrett-Connor E (1999) Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like growth factor-1 levels in women with and without breast cancer: the Rancho Bernardo Study. J Womens Health Gend Based Med 8:1265–1272PubMedGoogle Scholar
  20. 20.
    Kaaks R, Lundin E, Rinaldi S et al (2002) Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden. Cancer Causes Control 13:307–316PubMedCrossRefGoogle Scholar
  21. 21.
    Muti P, Quattrin T, Grant BJ et al (2002) Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev 11:1361–1368PubMedGoogle Scholar
  22. 22.
    Mink PJ, Shahar E, Rosamond WD et al (2002) Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study. Am J Epidemiol 156:349–352PubMedCrossRefGoogle Scholar
  23. 23.
    Keinan-Boker L, Bueno De Mesquita HB, Kaaks R et al (2003) Circulating levels of insulin-like growth factor I, its binding proteins -1,-2, -3, C-peptide and risk of postmenopausal breast cancer. Int J Cancer 106:90–95PubMedCrossRefGoogle Scholar
  24. 24.
    Toniolo P, Bruning PF, Akhmedkhanov A et al (2000) Serum insulin-like growth factor-I and breast cancer. Int J Cancer 88:828–832PubMedCrossRefGoogle Scholar
  25. 25.
    Verheus M, Peeters PH, Rinaldi S et al (2006) Serum C-peptide levels and breast cancer risk: Results from the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 119:659–667PubMedCrossRefGoogle Scholar
  26. 26.
    Renehan AG, Harvie M, Howell A (2006) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and breast cancer risk: eight years on. Endocr Relat Cancer 13:273–278PubMedCrossRefGoogle Scholar
  27. 27.
    Clemmons DR (2006) Involvement of insulin-like growth factor-I in the control of glucose homeostasis. Curr Opin Pharmacol 6:620–625PubMedCrossRefGoogle Scholar
  28. 28.
    Frystyk J (2004) Free insulin-like growth factors – measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res 14:337–375PubMedCrossRefGoogle Scholar
  29. 29.
    Gorber SC, Tremblay M, Moher D et al (2007) A comparison of direct vs. self-report measures for assessing height, weight and body mass index: a systematic review. Obes Rev 8:307–326PubMedCrossRefGoogle Scholar
  30. 30.
    Stattin P, Soderberg S, Biessy C et al (2004) Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat 86:191–196PubMedCrossRefGoogle Scholar
  31. 31.
    Mantzoros CS, Bolhke K, Moschos S et al (1999) Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 80:523–526PubMedCrossRefGoogle Scholar
  32. 32.
    Petridou E, Papadiamantis Y, Markopoulos C et al (2000) Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Control 11:383–388PubMedCrossRefGoogle Scholar
  33. 33.
    Tworoger SS, Eliassen AH, Kelesidis T et al (2007) Plasma adiponectin concentrations and risk of incident breast cancer. J Clin Endocrinol Metab 92:1510–1516PubMedCrossRefGoogle Scholar
  34. 34.
    Miyoshi Y, Funahashi T, Kihara S et al (2003) Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 9:5699–5704PubMedGoogle Scholar
  35. 35.
    Mantzoros C, Petridou E, Dessypris N et al (2004) Adiponectin and breast cancer risk. J Clin Endocrinol Metab 89:1102–1107PubMedCrossRefGoogle Scholar
  36. 36.
    Chen DC, Chung YF, Yeh YT et al (2006) Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 237:109–114PubMedCrossRefGoogle Scholar
  37. 37.
    Dieudonne MN, Bussiere M, Dos Santos E et al (2006) Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 345:271–279PubMedCrossRefGoogle Scholar
  38. 38.
    Peacock I (1984) Glycosylated haemoglobin: measurement and clinical use. J Clin Pathol 37:841–851PubMedCrossRefGoogle Scholar
  39. 39.
    Lin J, Ridker PM, Rifai N et al (2006) A prospective study of hemoglobin A1c concentrations and risk of breast cancer in women. Cancer Res 66:2869–2875PubMedCrossRefGoogle Scholar
  40. 40.
    Catalano S, Mauro L, Marsico S et al (2004) Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 279:19908–19915PubMedCrossRefGoogle Scholar
  41. 41.
    Manjer J, Kaaks R, Riboli E et al (2001) Risk of breast cancer in relation to anthropometry, blood pressure, blood lipids and glucose metabolism: a prospective study within the Malmo Preventive Project. Eur J Cancer Prev 10:33–42PubMedCrossRefGoogle Scholar
  42. 42.
    Jee SH, Ohrr H, Sull JW et al (2005) Fasting serum glucose level and cancer risk in Korean men and women. JAMA 293:194–202PubMedCrossRefGoogle Scholar
  43. 43.
    Althuis MD, Fergenbaum JH, Garcia-Closas M et al (2004) Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev 13:1558–1568PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Anne E. Cust
    • 1
    • 2
    • 3
  • Tanja Stocks
    • 4
    Email author
  • Annekatrin Lukanova
    • 5
  • Eva Lundin
    • 6
  • Göran Hallmans
    • 7
  • Rudolf Kaaks
    • 5
  • Håkan Jonsson
    • 8
  • Pär Stattin
    • 4
  1. 1.Centre for MEGA EpidemiologyThe University of MelbourneMelbourneAustralia
  2. 2.School of Public HealthThe University of SydneySydneyAustralia
  3. 3.Nutrition and Hormones UnitInternational Agency for Research on CancerLyonFrance
  4. 4.Department of Surgical and Perioperative Sciences, Urology and AndrologyUmeå UniversityUmeåSweden
  5. 5.Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany
  6. 6.Department of Medical Biosciences, PathologyUmeå UniversityUmeåSweden
  7. 7.Department of Public Health and Clinical Medicine, Nutritional ResearchUmeå UniversityUmeåSweden
  8. 8.Department of Radiation Sciences, OncologyUmeå UniversityUmeåSweden

Personalised recommendations