Skip to main content

Advertisement

SpringerLink
Log in

The vitamin D pathway and mammographic breast density among postmenopausal women

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

Abstract

Laboratory studies have demonstrated that vitamin D has a number of chemopreventive properties, and that these properties may be mediated or modified by other molecules in the vitamin D pathway, such as parathyroid hormone (PTH) or calcium. However, there is little epidemiologic data exploring the effects of vitamin D on breast cancer risk in the context of these other molecules. We examined a panel of molecules in the vitamin D pathway in relation to mammographic breast density, a marker of breast cancer risk, in the Wisconsin Breast Density Study. A total of 238 postmenopausal women (ages 55–70, with no history of postmenopausal hormone use) were enrolled from mammography clinics in Madison, Wisconsin. Subjects provided blood samples that were analyzed for levels of 25-hydroxy vitamin D [25(OH)D], PTH, insulin-like growth factor-1 (IGF-1), IGF-binding protein 3 (IGFBP-3), retinol, and calcium. Percent breast density was measured using Cumulus software. In age-adjusted analyses there was a positive association between 25(OH)D and percent breast density (P = 0.05; mean percent density = 11.3% vs. 15.6% for 1st vs. 4th quartile of 25(OH)D). Breast density was inversely associated with PTH (P = 0.05; 16.0% vs. 11.4% for Q1 vs. Q4) and positively associated with the IGF-1:IGFBP-3 molar ratio (P = 0.02; 11.9% vs. 15.6% for Q1 vs. Q4). However, these associations were all null after further adjustment for body mass index (BMI; P > 0.25). The independent relation between 25(OH)D and breast density remained null among subgroups defined by BMI and serum levels of retinol, calcium, and estradiol. These results suggest no strong independent associations between the circulating molecules of the vitamin D pathway and mammographic breast density in postmenopausal women. While it remains possible that vitamin D could influence breast cancer risk, our results suggest that such an effect would be mediated through pathways other than breast 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

Fig. 1

Similar content being viewed by others

References

  1. Deeb KK, Trump DL, Johnson CS (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7(9):684–700

    Article  PubMed  CAS  Google Scholar 

  2. Bertone-Johnson ER, Chen WY, Holick MF, Hollis BW, Colditz GA, Willett WC, Hankinson SE (2005) Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14(8):1991–1997

    Article  PubMed  CAS  Google Scholar 

  3. Engel P, Fagherazzi G, Boutten A, Dupre T, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F (2010) Serum 25(OH) vitamin D and risk of breast cancer: a nested case-control study from the French E3N cohort. Cancer Epidemiol Biomarkers Prev 19(9):2341–2350

    Article  PubMed  CAS  Google Scholar 

  4. Freedman DM, Chang SC, Falk RT, Purdue MP, Huang WY, McCarty CA, Hollis BW, Graubard BI, Berg CD, Ziegler RG (2008) Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 17(4):889–894

    Article  PubMed  CAS  Google Scholar 

  5. McCullough ML, Stevens VL, Patel R, Jacobs EJ, Bain EB, Horst RL, Gapstur SM, Thun MJ, Calle EE (2009) Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort. Breast Cancer Res 11(4):R64

    Article  PubMed  Google Scholar 

  6. Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, Rossouw J, Lane D, O’Sullivan MJ, Yasmeen S et al (2008) Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100(22):1581–1591

    Article  PubMed  CAS  Google Scholar 

  7. Giovannucci E (2005) The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 16(2):83–95

    Article  PubMed  Google Scholar 

  8. Almquist M, Manjer J, Bondeson L, Bondeson AG (2007) Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women. Cancer Causes Control 18(6):595–602

    Article  PubMed  Google Scholar 

  9. Birch MA, Carron JA, Scott M, Fraser WD, Fraser WD, Gallagher JA (1995) Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor expression and mitogenic responses in human breast cancer cell lines. Br J Cancer 72(1):90–95

    Article  PubMed  CAS  Google Scholar 

  10. Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4(7):505–518

    Article  PubMed  CAS  Google Scholar 

  11. Johansson S, Melhus H (2001) Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res 16(10):1899–1905

    Article  PubMed  CAS  Google Scholar 

  12. Boyd NF, Martin LJ, Bronskill M, Yaffe MJ, Duric N, Minkin S (2010) Breast tissue composition and susceptibility to breast cancer. J Natl Cancer Inst 102(16):1224–1237

    Article  PubMed  Google Scholar 

  13. Knight JA, Vachon CM, Vierkant RA, Vieth R, Cerhan JR, Sellers TA (2006) No association between 25-hydroxyvitamin D and mammographic density. Cancer Epidemiol Biomarkers Prev 15(10):1988–1992

    Article  PubMed  CAS  Google Scholar 

  14. Brisson J, Berube S, Diorio C, Sinotte M, Pollak M, Masse B (2007) Synchronized seasonal variations of mammographic breast density and plasma 25-hydroxyvitamin d. Cancer Epidemiol Biomarkers Prev 16(5):929–933

    Article  PubMed  CAS  Google Scholar 

  15. Green AK, Hankinson SE, Bertone-Johnson ER, Tamimi RM (2010) Mammographic density, plasma vitamin D levels and risk of breast cancer in postmenopausal women. Int J Cancer 127(3):667–674

    Article  PubMed  CAS  Google Scholar 

  16. Neuhouser ML, Bernstein L, Hollis BW, Xiao L, Ambs A, Baumgartner K, Baumgartner R, McTiernan A, Ballard-Barbash R (2010) Serum vitamin D and breast density in breast cancer survivors. Cancer Epidemiol Biomarkers Prev 19(2):412–417

    Article  PubMed  CAS  Google Scholar 

  17. Chai W, Maskarinec G, Cooney RV (2010) Serum 25-hydroxyvitamin D levels and mammographic density among premenopausal women in a multiethnic population. Eur J Clin Nutr 64(6):652–654

    Article  PubMed  CAS  Google Scholar 

  18. Sprague BL, Trentham-Dietz A, Gangnon RE, Buist DSM, Burnside ES, Aiello Bowles EJ, Stanczyk FZ, Sisney GS (2011) Circulating sex hormones and mammographic breast density among postmenopausal women. Hormones and Cancer 2(1):62–72

    Article  PubMed  CAS  Google Scholar 

  19. Chia VM, Quraishi SM, Graubard BI, Rubertone MV, Erickson RL, Stanczyk FZ, McGlynn KA (2008) Insulin-like growth factor 1, insulin-like growth factor-binding protein 3, and testicular germ-cell tumor risk. Am J Epidemiol 167(12):1438–1445

    Article  PubMed  Google Scholar 

  20. Troisi R, Lagiou P, Trichopoulos D, Xu B, Chie L, Stanczyk FZ, Potischman N, Adami HO, Hoover RN, Hsieh CC (2008) Cord serum estrogens, androgens, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 in Chinese and U.S. Caucasian neonates. Cancer Epidemiol Biomarkers Prev 17(1):224–231

    Article  PubMed  CAS  Google Scholar 

  21. Hollis BW (1997) Quantitation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D by radioimmunoassay using radioiodinated tracers. Methods Enzymol 282:174–186

    Article  PubMed  CAS  Google Scholar 

  22. Tsugawa N, Suhara Y, Kamao M, Okano T (2005) Determination of 25-hydroxyvitamin D in human plasma using high-performance liquid chromatography—tandem mass spectrometry. Anal Chem 77(9):3001–3007

    Article  PubMed  CAS  Google Scholar 

  23. Saenger AK, Laha TJ, Bremner DE, Sadrzadeh SM (2006) Quantification of serum 25-hydroxyvitamin D(2) and D(3) using HPLC-tandem mass spectrometry and examination of reference intervals for diagnosis of vitamin D deficiency. Am J Clin Pathol 125(6):914–920

    Article  PubMed  CAS  Google Scholar 

  24. Seamans KM, Hill TR, Wallace JM, Horigan G, Lucey AJ, Barnes MS, Taylor N, Bonham MP, Muldowney S, Duffy EM et al (2010) Cholecalciferol supplementation throughout winter does not affect markers of bone turnover in healthy young and elderly adults. J Nutr 140(3):454–460

    Article  PubMed  CAS  Google Scholar 

  25. Cashman KD, Wallace JM, Horigan G, Hill TR, Barnes MS, Lucey AJ, Bonham MP, Taylor N, Duffy EM, Seamans K et al (2009) Estimation of the dietary requirement for vitamin D in free-living adults >=64 y of age. Am J Clin Nutr 89(5):1366–1374

    Article  PubMed  CAS  Google Scholar 

  26. Taibi G, Nicotra CM (2002) Development and validation of a fast and sensitive chromatographic assay for all-trans-retinol and tocopherols in human serum and plasma using liquid–liquid extraction. J Chromatogr B Analyt Technol Biomed Life Sci 780(2):261–267

    Article  PubMed  CAS  Google Scholar 

  27. Goebelsmann U, Bernstein GS, Gale JA, Kletzky OA, Nakamura RM, Coulson AH, Korelitz JJ (1979) Serum gonadotropin, testosterone, estradiol and estrone levels prior to and following bilateral vasectomy. In: Lepow IH, Crozier R (eds) Vasectomy: immunologic and pathophysiologic effects in animals and man. Academic Press, New York

  28. Dorgan JF, Stanczyk FZ, Kahle LL, Brinton LA (2010) Prospective case-control study of premenopausal serum estradiol and testosterone levels and breast cancer risk. Breast Cancer Res 12(6):R98

    Article  PubMed  CAS  Google Scholar 

  29. Byng JW, Boyd NF, Fishell E, Jong RA, Yaffe MJ (1994) The quantitative analysis of mammographic densities. Phys Med Biol 39(10):1629–1638

    Article  PubMed  CAS  Google Scholar 

  30. Schafer JL (1997) Analysis of incomplete multivariate data. Chapman and Hall, New York

    Book  Google Scholar 

  31. Rubin DB (1987) Multiple imputation for nonresponse in surveys. John Wiley & Sons, New York

    Book  Google Scholar 

  32. Berube S, Diorio C, Verhoek-Oftedahl W, Brisson J (2004) Vitamin D, calcium, and mammographic breast densities. Cancer Epidemiol Biomarkers Prev 13(9):1466–1472

    PubMed  CAS  Google Scholar 

  33. Tseng M, Byrne C, Evers KA, Daly MB (2007) Dietary intake and breast density in high-risk women: a cross-sectional study. Breast Cancer Res 9(5):R72

    Article  PubMed  Google Scholar 

  34. Berube S, Diorio C, Masse B, Hebert-Croteau N, Byrne C, Cote G, Pollak M, Yaffe M, Brisson J (2005) Vitamin D and calcium intakes from food or supplements and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14(7):1653–1659

    Article  PubMed  CAS  Google Scholar 

  35. Masala G, Ambrogetti D, Assedi M, Giorgi D, Del Turco MR, Palli D (2006) Dietary and lifestyle determinants of mammographic breast density. A longitudinal study in a Mediterranean population. Int J Cancer 118(7):1782–1789

    Article  PubMed  CAS  Google Scholar 

  36. Vachon CM, Kushi LH, Cerhan JR, Kuni CC, Sellers TA (2000) Association of diet and mammographic breast density in the Minnesota breast cancer family cohort. Cancer Epidemiol Biomarkers Prev 9(2):151–160

    PubMed  CAS  Google Scholar 

  37. Thomson CA, Arendell LA, Bruhn RL, Maskarinec G, Lopez AM, Wright NC, Moll CE, Aickin M, Chen Z (2007) Pilot study of dietary influences on mammographic density in pre- and postmenopausal Hispanic and non-Hispanic white women. Menopause 14(2):243–250

    Article  PubMed  Google Scholar 

  38. Mishra G, McCormack V, Kuh D, Hardy R, Stephen A, dos Santos Silva I (2008) Dietary calcium and vitamin D intakes in childhood and throughout adulthood and mammographic density in a British birth cohort. Br J Cancer 99(9):1539–1543

    Article  PubMed  CAS  Google Scholar 

  39. Diorio C, Berube S, Byrne C, Masse B, Hebert-Croteau N, Yaffe M, Cote G, Pollak M, Brisson J (2006) Influence of insulin-like growth factors on the strength of the relation of vitamin D and calcium intakes to mammographic breast density. Cancer Res 66(1):588–597

    Article  PubMed  CAS  Google Scholar 

  40. Carron JA, Fraser WD, Gallagher JA (1997) PTHrP and the PTH/PTHrP receptor are co-expressed in human breast and colon tumours. Br J Cancer 76(8):1095–1098

    Article  PubMed  CAS  Google Scholar 

  41. Palmer M, Adami HO, Krusemo UB, Ljunghall S (1988) Increased risk of malignant diseases after surgery for primary hyperparathyroidism. A nationwide cohort study. Am J Epidemiol 127(5):1031–1040

    PubMed  CAS  Google Scholar 

  42. Pickard AL, Gridley G, Mellemkjae L, Johansen C, Kofoed-Enevoldsen A, Cantor KP, Brinton LA (2002) Hyperparathyroidism and subsequent cancer risk in Denmark. Cancer 95(8):1611–1617

    Article  PubMed  Google Scholar 

  43. Michels KB, Xue F, Brandt L, Ekbom A (2004) Hyperparathyroidism and subsequent incidence of breast cancer. Int J Cancer 110(3):449–451

    Article  PubMed  CAS  Google Scholar 

  44. Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE (2000) Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 60(14):3744–3748

    PubMed  CAS  Google Scholar 

  45. Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Minkin S (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87(8):876–882

    Article  PubMed  CAS  Google Scholar 

  46. Diorio C, Pollak M, Byrne C, Masse B, Hebert-Croteau N, Yaffe M, Cote G, Berube S, Morin C, Brisson J (2005) Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14(5):1065–1073

    Article  PubMed  CAS  Google Scholar 

  47. Maskarinec G, Williams AE, Kaaks R (2003) A cross-sectional investigation of breast density and insulin-like growth factor I. Int J Cancer 107(6):991–996

    Article  PubMed  CAS  Google Scholar 

  48. Cugini P, Coen G, Scavo D, Lucia P, Mazzaferro S, Bianchini G, Massimetti C, Donato G (1984) Circannual versus seasonal variations of longitudinally sampled 25-hydroxycholecalciferol serum levels. Biochem Med 32(1):22–29

    Article  PubMed  CAS  Google Scholar 

  49. Holick MF (2004) Vitamin D: Importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79(3):362–371

    PubMed  CAS  Google Scholar 

  50. Kotsopoulos J, Tworoger SS, Campos H, Chung FL, Clevenger CV, Franke AA, Mantzoros CS, Ricchiuti V, Willett WC, Hankinson SE et al (2010) Reproducibility of plasma and urine biomarkers among premenopausal and postmenopausal women from the Nurses’ Health Studies. Cancer Epidemiol Biomarkers Prev 19(4):938–946

    Article  PubMed  CAS  Google Scholar 

  51. Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, Grimnes G (2010) Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. Am J Epidemiol 171(8):903–908

    Article  PubMed  Google Scholar 

  52. Tangrea J, Helzlsouer K, Pietinen P, Taylor P, Hollis B, Virtamo J, Albanes D (1997) Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control 8(4):615–625

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Cancer Institute (CA139548, CA014520), the Department of Defense (BC062649), and the Susan G. Komen Foundation (FAS0703857). Dr. Sprague is supported by a fellowship from the American Society of Preventive Oncology sponsored by the Prevent Cancer Foundation and the Susan G. Komen Foundation. The authors would like to thank Kristi Klein and the staff of UW Health Clinics, Dr. Walter Peppler, Eva Baird, and Lori Wollett and staff of the UW OCT for their assistance in subject recruitment and data collection; Dr. Marty Kanarek, John Hampton, Tammy LeCaire, Tanya Watson, Matt Walsh, Jane Maney, and Cecilia Bellcross for study-related advice; Dr. Martin Yaffe and Chris Peressotti for assistance in breast density measurements; Dr. Karen Cruickshanks, Carla Schubert, and Scott Nash for assistance in sample storage; and Julie McGregor, Kathy Peck, and Dawn Fitzgibbons for study support.

Conflict of interest

The authors report no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Vermont, Burlington, VT, 05401, USA

    Brian L. Sprague

  2. Department of Population Health Sciences, University of Wisconsin, Madison, WI, 53726, USA

    Brian L. Sprague, Amy Trentham-Dietz, Ronald E. Gangnon & Halcyon G. Skinner

  3. University of Wisconsin Carbone Cancer Center, Madison, WI, 53726, USA

    Amy Trentham-Dietz, Ronald E. Gangnon, Elizabeth S. Burnside & Halcyon G. Skinner

  4. Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, 53726, USA

    Ronald E. Gangnon

  5. Group Health Research Institute, Seattle, WA, 98101, USA

    Diana S. M. Buist & Erin J. Aiello Bowles

  6. Department of Radiology, University of Wisconsin, Madison, WI, 53726, USA

    Elizabeth S. Burnside & Gale S. Sisney

  7. Departments of Obstetrics and Gynecology and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Frank Z. Stanczyk

  8. Office of Health Promotion Research, 1 South Prospect St, Rm 4428B, Burlington, VT, 05401, USA

    Brian L. Sprague

Authors
  1. Brian L. Sprague
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy Trentham-Dietz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald E. Gangnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diana S. M. Buist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth S. Burnside
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Erin J. Aiello Bowles
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frank Z. Stanczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gale S. Sisney
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Halcyon G. Skinner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian L. Sprague.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sprague, B.L., Trentham-Dietz, A., Gangnon, R.E. et al. The vitamin D pathway and mammographic breast density among postmenopausal women. Breast Cancer Res Treat 131, 255–265 (2012). https://doi.org/10.1007/s10549-011-1726-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1726-5

Keywords

Search

Navigation