Skip to main content

Advertisement

SpringerLink
Log in

Circulating levels of inflammatory markers and mammographic density among postmenopausal women

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Mammographic density is strongly associated with breast cancer risk. Inflammation is involved in breast carcinogenesis, perhaps through effects on mammographic density. We evaluated associations between inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) and mammographic density among postmenopausal women. Plasma IL-6, TNF-α, and CRP levels were measured in 145 women with benign breast disease (benign controls) and 397 women with a negative screening mammogram (well controls) enrolled in the Mammograms and Masses Study. Associations between the inflammatory markers and mammographic density were evaluated separately for benign and well controls through correlation analyses and linear regressions. Age-adjusted mean CRP levels were higher among benign controls (2.07 μg/ml) compared to well controls (1.63 μg/ml; P = 0.02), while IL-6 and TNF-α levels were similar between groups. Using linear regression, IL-6, TNF-α, and CRP were not statistically significantly associated with dense breast area within either group. Statistically significant positive associations were observed between all three markers and nondense breast area in both groups; statistically significant negative associations were observed between IL-6 and percent density among benign controls, and between all three markers and percent density among well controls. These associations were all attenuated and non-significant upon adjustment for body mass index. IL-6, TNF-α, and CRP levels were not independently associated with dense breast area, nondense breast area, or percent density in this study population. Our results suggest that these inflammatory factors do not impact breast carcinogenesis through independent effects on mammographic density.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ANOVA:

Analysis of variance

BMI:

Body mass index

COX-2:

Cyclooxygenase-2

CRP:

C-reactive protein

ELISA:

Enzyme-linked immunosorbent assay

IL-6:

Interleukin-6

LCBR:

Laboratory for Biochemsitry Research

MAMS:

Mammograms and Masses Study

NSAID:

Non-steroidal anti-inflammatory drug

TNF-α:

Tumor necrosis factor alpha

References

  1. Boyd NF, Martin LJ, Rommens JM et al (2009) Mammographic density: a heritable risk factor for breast cancer. Methods Mol Biol 472:343–360

    Article  PubMed  Google Scholar 

  2. Wolfe JN (1976) Breast patterns as an index of risk for developing breast cancer. Am J Roentgenol 126:1130–1137

    CAS  Google Scholar 

  3. Wolfe JN (1969) The prominent duct pattern as an indicator of cancer risk. Oncology 23:149–158

    Article  PubMed  CAS  Google Scholar 

  4. Torres-Mejia G, De Stavola B, Allen DS et al (2005) Mammographic features and subsequent risk of breast cancer: a comparison of qualitative and quantitative evaluations in the Guernsey prospective studies. Cancer Epidemiol Biomarkers Prev 14:1052–1059

    Article  PubMed  Google Scholar 

  5. Kato I, Beinart C, Bleich A et al (1995) A nested case-control study of mammographic patterns, breast volume, and breast cancer. Cancer Causes Control 6:431–438

    Article  PubMed  CAS  Google Scholar 

  6. Byrne C, Schairer C, Wolfe J et al (1995) Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87:1622–1629

    Article  PubMed  CAS  Google Scholar 

  7. Boyd NF, Dite GS, Stone J et al (2002) Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347:886–894

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Morimoto LM, White E, Chen Z et al (2002) Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative. Cancer Causes Control 13:741–751

    Article  PubMed  Google Scholar 

  10. Harvey JA, Pinkerton JV, Herman CR (1997) Short-term cessation of hormone replacement therapy and improvement of mammographic specificity. J Natl Cancer Inst 89:1623–1625

    Article  PubMed  CAS  Google Scholar 

  11. Ursin G, Parisky YR, Pike MC et al (2001) Mammographic density changes during the menstrual cycle. Cancer Epidemiol Biomarkers Prev 10:141–142

    PubMed  CAS  Google Scholar 

  12. Key T, Appleby P, Barnes I et al (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616

    PubMed  CAS  Google Scholar 

  13. Kaaks R, Rinaldi S, Key TJ et al (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12:1071–1082

    Article  PubMed  CAS  Google Scholar 

  14. Reeves GK, Beral V, Green J et al (2006) Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 7:910–918

    Article  PubMed  CAS  Google Scholar 

  15. Shah NR, Borenstein J, Dubois RW (2005) Postmenopausal hormone therapy and breast cancer: a systematic review and meta-analysis. Menopause 12:668–678

    Article  PubMed  Google Scholar 

  16. Cotterchio M, Kreiger N, Sloan M et al (2001) Nonsteroidal anti-inflammatory drug use and breast cancer risk. Cancer Epidemiol Biomarkers Prev 10:1213–1217

    PubMed  CAS  Google Scholar 

  17. Harris RE, Chlebowski RT, Jackson RD et al (2003) Breast cancer and nonsteroidal anti-inflammatory drugs: prospective results from the Women’s Health Initiative. Cancer Res 63:6096–6101

    PubMed  CAS  Google Scholar 

  18. Khuder SA, Mutgi AB (2001) Breast cancer and NSAID use: a meta-analysis. Br J Cancer 84:1188–1192

    Article  PubMed  CAS  Google Scholar 

  19. Terry MB, Gammon MD, Zhang FF et al (2004) Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291:2433–2440

    Article  PubMed  CAS  Google Scholar 

  20. Gallicchio L, McSorley MA, Newschaffer CJ et al (2006) Nonsteroidal antiinflammatory drugs, cyclooxygenase polymorphisms, and the risk of developing breast carcinoma among women with benign breast disease. Cancer 106:1443–1452

    Article  PubMed  CAS  Google Scholar 

  21. DuBois RN (2004) Aspirin and breast cancer prevention: the estrogen connection. JAMA 291:2488–2489

    Article  PubMed  CAS  Google Scholar 

  22. Reed MJ, Purohit A (1997) Breast cancer and the role of cytokines in regulating estrogen synthesis: an emerging hypothesis. Endocr Rev 18:701–715

    Article  PubMed  CAS  Google Scholar 

  23. Purohit A, Reed MJ (2002) Regulation of estrogen synthesis in postmenopausal women. Steroids 67:979–983

    Article  PubMed  CAS  Google Scholar 

  24. Carr BR, Bradshaw KD (2001) Disorders of the ovary and female reproductive tract. In: Braunwald E, Fauci AS, Kasper DL et al (eds) Harrison’s principles of internal medicine, 15th edn. McGraw-Hill, New York, NY

    Google Scholar 

  25. Bogaty P, Brophy JM, Noel M et al (2004) Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study. Circulation 110:934–939

    Article  PubMed  CAS  Google Scholar 

  26. Il’yasova D, Colbert LH, Harris TB et al (2005) Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomarkers Prev 14:2413–2418

    Article  PubMed  Google Scholar 

  27. 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 20:15–26

    Article  PubMed  Google Scholar 

  28. Bhandare D, Nayar R, Bryk M et al (2005) Endocrine biomarkers in ductal lavage samples from women at high risk for breast cancer. Cancer Epidemiol Biomarkers Prev 14:2620–2627

    Article  PubMed  CAS  Google Scholar 

  29. Gonullu G, Ersoy C, Ersoy A et al (2005) Relation between insulin resistance and serum concentrations of IL-6 and TNF-alpha in overweight or obese women with early stage breast cancer. Cytokine 31:264–269

    Article  PubMed  CAS  Google Scholar 

  30. Caras I, Grigorescu A, Stavaru C et al (2004) Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother 53:1146–1152

    Article  PubMed  CAS  Google Scholar 

  31. DeKeyser FG, Wainstock JM, Rose L et al (1998) Distress, symptom distress, and immune function in women with suspected breast cancer. Oncol Nurs Forum 25:1415–1422

    PubMed  CAS  Google Scholar 

  32. Krajcik RA, Massardo S, Orentreich N (2003) No association between serum levels of tumor necrosis factor-alpha (TNF-alpha) or the soluble receptors sTNFR1 and sTNFR2 and breast cancer risk. Cancer Epidemiol Biomarkers Prev 12:945–946

    PubMed  CAS  Google Scholar 

  33. Campbell MJ, Scott J, Maecker HT et al (2005) Immune dysfunction and micrometastases in women with breast cancer. Breast Cancer Res Treat 91:163–171

    Article  PubMed  CAS  Google Scholar 

  34. Sheen-Chen SM, Chen WJ, Eng HL et al (1997) Serum concentration of tumor necrosis factor in patients with breast cancer. Breast Cancer Res Treat 43:211–215

    Article  PubMed  CAS  Google Scholar 

  35. Allin KH, Bojesen SE, Nordestgaard BG (2009) Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol 27:2217–2224

    Article  PubMed  CAS  Google Scholar 

  36. Zhang SM, Lin J, Cook NR et al (2007) C-reactive protein and risk of breast cancer. J Natl Cancer Inst 99:890–894

    Article  PubMed  CAS  Google Scholar 

  37. Trichopoulos D, Psaltopoulou T, Orfanos P et al (2006) Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiol Biomarkers Prev 15:381–384

    Article  PubMed  CAS  Google Scholar 

  38. Siemes C, Visser LE, Coebergh JW et al (2006) C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol 24:5216–5222

    Article  PubMed  CAS  Google Scholar 

  39. Lithgow D, Nyamathi A, Elashoff D et al (2007) C-reactive protein in nipple aspirate fluid associated with Gail model factors. Biol Res Nurs 9:108–116

    Article  PubMed  CAS  Google Scholar 

  40. Reeves KW, Gierach GL, Modugno F (2007) Recreational physical activity and mammographic breast density characteristics. Cancer Epidemiol Biomarkers Prev 16:934–942

    Article  PubMed  Google Scholar 

  41. Hudson AG, Gierach GL, Modugno F et al (2008) Nonsteroidal anti-inflammatory drug use and serum total estradiol in postmenopausal women. Cancer Epidemiol Biomarkers Prev 17:680–687

    Article  PubMed  CAS  Google Scholar 

  42. Palomares MR, Machia JR, Lehman CD et al (2006) Mammographic density correlation with Gail model breast cancer risk estimates and component risk factors. Cancer Epidemiol Biomarkers Prev 15:1324–1330

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  44. Boyd NF, Martin LJ, Sun L et al (2006) Body size, mammographic density, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 15:2086–2092

    Article  PubMed  Google Scholar 

  45. Reeves KW, Stone RA, Modugno F et al (2009) Longitudinal association of anthropometry with mammographic breast density in the Study of Women’s Health Across the Nation. Int J Cancer 124:1169–1177

    Article  PubMed  CAS  Google Scholar 

  46. 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. doi:10.1002/ijc.25676

  47. Himmerich H, Fulda S, Linseisen J et al (2006) TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population. Eur Cytokine Netw 17:196–201

    PubMed  CAS  Google Scholar 

  48. Bochud M, Marquant F, Marques-Vidal PM et al (2009) Association between C-reactive protein and adiposity in women. J Clin Endocrinol Metab 94:3969–3977

    Article  PubMed  CAS  Google Scholar 

  49. Weisberg SP, McCann D, Desai M et al (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    PubMed  CAS  Google Scholar 

  50. Sunderkotter C, Steinbrink K, Goebeler M et al (1994) Macrophages and angiogenesis. J Leukoc Biol 55:410–422

    PubMed  CAS  Google Scholar 

  51. Garcia-Macedo R, Sanchez-Munoz F, Almanza-Perez JC et al (2008) Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3T3–L1 cells. Eur J Pharmacol 587:317–321

    Article  PubMed  CAS  Google Scholar 

  52. Kolsum U, Roy K, Starkey C et al (2009) The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year. Int J Chron Obstruct Pulmon Dis 4:149–156

    PubMed  CAS  Google Scholar 

  53. Karakas M, Baumert J, Greven S et al (2010) Reproducibility in serial C-reactive protein and interleukin-6 measurements in post-myocardial infarction patients: results from the AIRGENE study. Clin Chem 56:861–864

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Department of Defense Grant BC050518 and National Institutes of Health Grant R25 CA057703. Additional support was provided by funds received from the National Institutes of Health/National Center for Research Resources/General Clinical Research Center Grant MO1-RR000056.

Author information

Authors and Affiliations

  1. Department of Public Health, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA

    Katherine W. Reeves

  2. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Joel L. Weissfeld, Francesmary Modugno & Brenda Diergaarde

  3. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Joel L. Weissfeld & Brenda Diergaarde

  4. 410 Arnold House, 715 North Pleasant Street, Amherst, MA, 01003, USA

    Katherine W. Reeves

Authors
  1. Katherine W. Reeves
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joel L. Weissfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesmary Modugno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brenda Diergaarde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine W. Reeves.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reeves, K.W., Weissfeld, J.L., Modugno, F. et al. Circulating levels of inflammatory markers and mammographic density among postmenopausal women. Breast Cancer Res Treat 127, 555–563 (2011). https://doi.org/10.1007/s10549-010-1249-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-1249-5

Keywords

Search

Navigation