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Association between sex hormones, glucose homeostasis, adipokines, and inflammatory markers and mammographic density among postmenopausal women

  • Epidemiology
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Abstract

The biological mechanisms underlying the relationship between mammographic density and breast cancer risk are unknown. Our objective was to examine the association between mammographic density and circulating factors that are putative breast cancer intermediate endpoints. Biologic data from a year-long aerobic exercise intervention trial conducted in 302 postmenopausal women aged 50–74 years were analyzed. Sex hormones, markers of glucose homeostasis, inflammatory markers, and adipokines were assayed in fasting blood drawn at baseline and after 1 year. Area and volumetric measurements of mammographic dense fibroglandular and nondense fatty tissue were made. Multiple linear regression was used to examine the association between the circulating factors and mammographic measures and partial correlations were estimated. Mammographic nondense volume was positively correlated with concentrations of estradiol (r = 0.28), estrone (r = 0.13), insulin (r = 0.41), glucose (r = 0.15), leptin (r = 0.49), and C-reactive protein (r = 0.22), and negatively correlated with sex hormone binding globulin (r = −0.30) and adiponectin (r = −0.12) but correlations became null after adjustment for overall body adiposity as represented by body mass index and waist circumference. With adjustment for overall adiposity, mammographic dense volume, a measure that represents fibroglandular tissue, was negatively correlated with leptin (r = −0.19) and C-reactive protein (r = −0.19). As expected, circulating factors originating from or correlated with adipose tissue were also correlated with mammographic measures of breast adipose tissue, but not after adjustment for overall body adiposity. Interpreting correlations between adiposity-derived factors and mammographic measures whose validity may be affected by adiposity is problematic. To rectify this problem, future studies with very good measures of the volume of fibroglandular tissue in the breast will be necessary.

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References

  1. McCormack VA, dos Santos Silva I (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15(6):1159–1169

    Article  PubMed  Google Scholar 

  2. Boyd NF, Rommens JM, Vogt K et al (2005) Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 6(10):798–808

    Article  PubMed  Google Scholar 

  3. Martin LJ, Boyd NF (2008) Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res 10(1):201

    Article  PubMed  Google Scholar 

  4. McTiernan A, Martin CF, Peck JD et al (2005) Estrogen-plus-progestin use and mammographic density in postmenopausal women: women’s health initiative randomized trial. J Natl Cancer Inst 97(18):1366–1376

    Article  PubMed  CAS  Google Scholar 

  5. Greendale GA, Reboussin BA, Slone S et al (2003) Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst 95(1):30–37

    Article  PubMed  CAS  Google Scholar 

  6. Martin LJ, Minkin S, Boyd NF (2009) Hormone therapy, mammographic density, and breast cancer risk. Maturitas 64(1):20–26

    Article  PubMed  CAS  Google Scholar 

  7. Boyd NF, Stone J, Martin LJ et al (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87(8):876–882

    Article  PubMed  CAS  Google Scholar 

  8. Bremnes Y, Ursin G, Bjurstam N et al (2007) Endogenous sex hormones, prolactin and mammographic density in postmenopausal Norwegian women. Int J Cancer 121(11):2506–2511

    Article  PubMed  CAS  Google Scholar 

  9. Tamimi RM, Hankinson SE, Colditz GA, Byrne C (2005) Endogenous sex hormone levels and mammographic density among postmenopausal women. Cancer Epidemiol Biomarkers Prev 14(11 Pt 1):2641–2647

    Article  PubMed  CAS  Google Scholar 

  10. Verheus M, Peeters PH, van Noord PA et al (2007) No relationship between circulating levels of sex steroids and mammographic breast density: the Prospect-EPIC cohort. Breast Cancer Res 9(4):R53

    Article  PubMed  Google Scholar 

  11. Warren R, Skinner J, Sala E et al (2006) Associations among mammographic density, circulating sex hormones, and polymorphisms in sex hormone metabolism genes in postmenopausal women. Cancer Epidemiol Biomarkers Prev 15(8):1502–1508

    Article  PubMed  CAS  Google Scholar 

  12. Sprague BL, Trentham-Dietz A, Gangnon RE et al (2011) Circulating sex hormones and mammographic breast density among postmenopausal women. Horm Cancer 2(1):62–72

    Article  PubMed  CAS  Google Scholar 

  13. McCormack VA, Dowsett M, Folkerd E et al (2009) Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women. Breast Cancer Res 11(3):R38

    Article  PubMed  Google Scholar 

  14. Johansson H, Gandini S, Bonanni B et al (2007) Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women. Breast Cancer Res Treat 108(1):57–67

    Article  PubMed  Google Scholar 

  15. Greendale GA, Palla SL, Ursin G et al (2005) The association of endogenous sex steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study. Am J Epidemiol 162(9):826–834

    Article  PubMed  Google Scholar 

  16. Aiello EJ, Tworoger SS, Yasui Y et al (2005) Associations among circulating sex hormones, insulin-like growth factor, lipids, and mammographic density in postmenopausal women. Cancer Epidemiol Biomarkers Prev 14(6):1411–1417

    Article  PubMed  CAS  Google Scholar 

  17. Stuedal A, Ursin G, Veierod MB et al (2006) Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study. Breast Cancer Res 8(5):R55

    Article  PubMed  Google Scholar 

  18. Reeves KW, Weissfeld JL, Modugno F, Diergaarde B (2011) Circulating levels of inflammatory markers and mammographic density among postmenopausal women. Breast Cancer Res Treat 127(2):555–563

    Article  PubMed  CAS  Google Scholar 

  19. Haars G, van Noord PA, van Gils CH et al (2005) Measurements of breast density: no ratio for a ratio. Cancer Epidemiol Biomarkers Prev 14(11 Pt 1):2634–2640

    Article  PubMed  Google Scholar 

  20. Friedenreich CM, Woolcott CG, McTiernan A et al (2010) The Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. J Clin Oncol 28:1458–1466

    Article  PubMed  CAS  Google Scholar 

  21. Friedenreich C, Neilson HK, Woolcott CG et al (2011) Alberta physical activity and breast cancer prevention trial: inflammatory marker changes in a year-long exercise intervention among postmenopausal women. Cancer Prev Res (Phila) 5(1):98–108

    Article  Google Scholar 

  22. Friedenreich CM, Neilson HK, Woolcott CG et al (2011) Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women. Endocr Relat Cancer 18(3):357–369

    Article  PubMed  CAS  Google Scholar 

  23. Woolcott CG, Courneya KS, Boyd NF et al (2010) Mammographic density change with 1 year of aerobic exercise among postmenopausal women: a randomized controlled trial. Cancer Epidemiol Biomarkers Prev 19(4):1112–1121

    Article  PubMed  Google Scholar 

  24. Boyd N, Martin L, Gunasekara A et al (2009) Mammographic density and breast cancer risk: evaluation of a novel method of measuring breast tissue volumes. Cancer Epidemiol Biomarkers Prev 18(6):1754–1762

    Article  PubMed  Google Scholar 

  25. Stanczyk FZ, Lee JS, Santen RJ (2007) Standardization of steroid hormone assays: why, how, and when? Cancer Epidemiol Biomarkers Prev 16(9):1713–1719

    Article  PubMed  CAS  Google Scholar 

  26. Goebelsmann U, Horton R, Mestman JH et al (1973) Male pseudohermaphroditism due to testicular 17-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 36(5):867–879

    Article  PubMed  CAS  Google Scholar 

  27. Stanczyk FZ, Slater CC, Ramos DE et al (2009) Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term oral dehydroepiandrosterone treatment in postmenopausal women. Menopause 16(2):272–278

    Article  PubMed  Google Scholar 

  28. Rinaldi S, Geay A, Dechaud H et al (2002) Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiol Biomarkers Prev 11(10 Pt 1):1065–1071

    PubMed  CAS  Google Scholar 

  29. Vermeulen A, Verdonck L, Kaufman JM (1999) A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84(10):3666–3672

    Article  PubMed  CAS  Google Scholar 

  30. Byng JW, Boyd NF, Fishell E et al (1994) The quantitative analysis of mammographic densities. Phys Med Biol 39:1629–1638

    Article  PubMed  CAS  Google Scholar 

  31. Pawluczyk O, Augustine BJ, Yaffe MJ et al (2003) A volumetric method for estimation of breast density on digitized screen-film mammograms. Med Phys 30(3):352–364

    Article  PubMed  Google Scholar 

  32. Yaffe MJ (2008) Measurement of mammographic density. Breast Cancer Res 10(3):209

    Article  PubMed  Google Scholar 

  33. Diet History Questionnaire: Canadian version (2006). http://www.riskfactor.cancer.gov/DHQ/forms/canadian/index.html. Accessed 15 April 2013

  34. National Cancer Institute, Risk Factor Monitoring and Methods Branch Division of Cancer Control and Population Sciences. Diet History Questionnaire (DHQ) (2002). http://www.riskfactor.cancer.gov/DHQ/forms/files/shared/dhq1.2007.sample.pdf. Accessed 15 April 2013

  35. Woolcott CG, Cook LS, Courneya KS et al (2010) Associations of overall and abdominal adiposity with area and volumetric mammographic measures among postmenopausal women. Int J Cancer 129(2):440–448

    Article  PubMed  Google Scholar 

  36. Khandekar MJ, Cohen P, Spiegelman BM (2011) Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 11(12):886–895

    Article  PubMed  CAS  Google Scholar 

  37. Endogenous Hormones and Breast Cancer Collaborative Group (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95(16):1218–1226

    Article  Google Scholar 

  38. Vachon CM, Brandt KR, Ghosh K et al (2007) Mammographic breast density as a general marker of breast cancer risk. Cancer Epidemiol Biomarkers Prev 16(1):43–49

    Article  PubMed  Google Scholar 

  39. Verheus M, Peeters PH, Kaaks R et al (2007) Premenopausal insulin-like growth factor-I serum levels and changes in breast density over menopause. Cancer Epidemiol Biomarkers Prev 16(3):451–457

    Article  PubMed  CAS  Google Scholar 

  40. Martin LJ, Greenberg CV, Kriukov V et al (2009) Effect of a low-fat, high-carbohydrate dietary intervention on change in mammographic density over menopause. Breast Cancer Res Treat 113(1):163–172

    Article  PubMed  CAS  Google Scholar 

  41. Haakensen VD, Biong M, Lingjaerde OC et al (2010) Expression levels of uridine 5′-diphospho-glucuronosyltransferase genes in breast tissue from healthy women are associated with mammographic density. Breast Cancer Res 12(4):R65

    Article  PubMed  Google Scholar 

  42. Edlefsen KL, Jackson RD, Prentice RL et al (2010) The effects of postmenopausal hormone therapy on serum estrogen, progesterone, and sex hormone-binding globulin levels in healthy postmenopausal women. Menopause 17(3):622–629

    PubMed  Google Scholar 

  43. McTiernan A, Chlebowski RT, Martin C et al (2009) Conjugated equine estrogen influence on mammographic density in postmenopausal women in a substudy of the Women’s Health Initiative randomized trial. J Clin Oncol 27(36):6135–6143

    Article  PubMed  Google Scholar 

  44. Conroy SM, Butler LM, Harvey D et al (2011) Metabolic syndrome and mammographic density: the Study of Women’s Health Across the Nation. Int J Cancer 129(7):1699–1707

    Article  PubMed  CAS  Google Scholar 

  45. Sellers TA, Jensen LE, Vierkant RA et al (2007) Association of diabetes with mammographic breast density and breast cancer in the Minnesota breast cancer family study. Cancer Causes Control 18(5):505–515

    Article  PubMed  Google Scholar 

  46. Diorio C, Pollak M, Byrne C et al (2005) Levels of C-peptide and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14(11 Pt 1):2661–2664

    Article  PubMed  CAS  Google Scholar 

  47. Hankinson SE, Willett WC, Manson JE et al (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90(17):1292–1299

    Article  PubMed  CAS  Google Scholar 

  48. Gunter MJ, Hoover DR, Yu H et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101(1):48–60

    Article  PubMed  CAS  Google Scholar 

  49. Maskarinec G, Woolcott C, Steude JS et al (2010) The relation of leptin and adiponectin with breast density among premenopausal women. Eur J Cancer Prev 19(1):55–60

    Article  PubMed  CAS  Google Scholar 

  50. Furberg AS, Jasienska G, Bjurstam N et al (2005) Metabolic and hormonal profiles: HDL cholesterol as a plausible biomarker of breast cancer risk. The Norwegian EBBA Study. Cancer Epidemiol Biomarkers Prev 14(1):33–40

    PubMed  CAS  Google Scholar 

  51. Macis D, Gandini S, Guerrieri-Gonzaga A et al (2012) Prognostic effect of circulating adiponectin in a randomized 2 × 2 trial of low-dose Tamoxifen and Fenretinide in premenopausal women at risk for breast cancer. J Clin Oncol 30(2):151–157

    Article  PubMed  CAS  Google Scholar 

  52. Heikkila K, Harris R, Lowe G et al (2009) Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control 20(1):15–26

    Article  PubMed  Google Scholar 

  53. McTiernan A, Wang CY, Sorensen B et al (2009) No effect of aspirin on mammographic density in a randomized controlled clinical trial. Cancer Epidemiol Biomarkers Prev 18(5):1524–1530

    Article  PubMed  CAS  Google Scholar 

  54. Terry MB, Buist DS, Trentham-Dietz A et al (2008) Nonsteroidal anti-inflammatory drugs and change in mammographic density: a cohort study using pharmacy records on over 29,000 postmenopausal women. Cancer Epidemiol Biomarkers Prev 17(5):1088–1095

    Article  PubMed  CAS  Google Scholar 

  55. Maskarinec G, Urano Y, Gill J, Kolonel LN (2008) Nonsteroidal anti-inflammatory drugs (NSAIDs) and mammographic density. Breast Cancer Res Treat 112(1):133–139

    Article  PubMed  CAS  Google Scholar 

  56. Yang WT, Lewis MT, Hess K et al (2010) Decreased TGF beta signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat 119(2):305–314

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was financially supported through research grants from the Canadian Breast Cancer Research Alliance (#13576 and #017468) and the Alberta Cancer Foundation (#22170). Dr. Friedenreich was supported by career awards from Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. Drs. Courneya and Cook were supported by the Canada Research Chairs Program. The research programs of Drs. Friedenreich and Courneya have been supported by a Team Grant from the Sociobehavioural Research Program with funds from the Canadian Cancer Society. Dr. Woolcott was funded by National Cancer Institute of Canada/Canadian Cancer Society Studentship for the period in which the bulk of this work was done. We also sincerely thank the participants in the Alberta Physical Activity and Breast Cancer Prevention Trial. Initial study set-up was done by Kim van der Hoek and Marla Orenstein and study coordination by Rosemary Crosby and Ame-Lia Tamburrini in Calgary. Data verification was done by Sandra Blitz. Mammograms were pulled, digitized and analyzed by Christina Edwards, Jenny Gougeon, and Anoma Gunasekara. Final manuscript set-up was done by Heather Neilson.

Ethical Standards

This study was conducted in accordance with the principles set out in Canada’s Tricouncil Policy Statement–Ethical Conduct for Research Involving Humans. Clinicaltrials.gov identifier: NCT00522262.

Conflict of interest

M.J.Y. is a founder and stockholder in Matakina Technologies, a company that produces software products for measurement of mammographic density. Neither the company nor its products were involved directly in this project. The remaining authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Obstetrics & Gynaecology and Pediatrics, Dalhousie University, Halifax, NS, Canada

    Christy G. Woolcott

  2. Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB, Canada

    Kerry S. Courneya

  3. Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada

    Norman F. Boyd

  4. Sunnybrook Research Institute, Toronto, ON, Canada

    Martin J. Yaffe

  5. Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, WA, USA

    Anne McTiernan

  6. Department of Statistics, University of British Columbia, Vancouver, BC, Canada

    Rollin Brant

  7. Southern Medical Program, University of British Columbia (Okanagan Campus), Kelowna, BC, Canada

    Charlotte A. Jones

  8. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Frank Z. Stanczyk

  9. Cross Cancer Institute, Alberta Cancer Board, Edmonton, AB, Canada

    Tim Terry

  10. Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA

    Linda S. Cook

  11. Alberta Health Services, Calgary, AB, Canada

    Linda S. Cook, Qinggang Wang & Christine M. Friedenreich

  12. Department of Population Health Research, Alberta Health Services-Cancer Care, Box ACB, 2210-2nd St. SW, Calgary, AB, T2S 3C3, Canada

    Christine M. Friedenreich

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  1. Christy G. Woolcott
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  2. Kerry S. Courneya
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  3. Norman F. Boyd
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  4. Martin J. Yaffe
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  5. Anne McTiernan
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  6. Rollin Brant
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  7. Charlotte A. Jones
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  8. Frank Z. Stanczyk
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  9. Tim Terry
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  10. Linda S. Cook
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  11. Qinggang Wang
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  12. Christine M. Friedenreich
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Correspondence to Christine M. Friedenreich.

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Woolcott, C.G., Courneya, K.S., Boyd, N.F. et al. Association between sex hormones, glucose homeostasis, adipokines, and inflammatory markers and mammographic density among postmenopausal women. Breast Cancer Res Treat 139, 255–265 (2013). https://doi.org/10.1007/s10549-013-2534-x

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  • DOI: https://doi.org/10.1007/s10549-013-2534-x

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