Skip to main content
Top
Published in: Cancer Causes & Control 7/2014

01-07-2014 | Original paper

Plasma free 25-hydroxyvitamin D, vitamin D binding protein, and risk of breast cancer in the Nurses’ Health Study II

Authors: Jun Wang, A. Heather Eliassen, Donna Spiegelman, Walter C. Willett, Susan E. Hankinson

Published in: Cancer Causes & Control | Issue 7/2014

Login to get access

Abstract

Purpose

Prior prospective studies, including our own, have evaluated total plasma 25-hydroxyvitamin D [25(OH)D] and breast cancer risk with inconsistent results. However, recent studies suggest that some vitamin D functions may be more relevant to the unbound (free) fraction of 25(OH)D. Vitamin D binding protein (DBP) influences the free 25(OH)D levels and thus possibly the biological activities of vitamin D.

Methods

We conducted a case–control study nested within the Nurses’ Health Study II to evaluate the association of plasma free 25(OH)D and DBP with breast cancer risk in predominantly premenopausal women. Plasma samples were assayed for 25(OH)D and DBP in 584 case–control pairs. Free 25(OH)D levels were calculated based on plasma levels of total 25(OH)D, DBP, and a constant value representing average albumin levels. Conditional logistic regression was used to estimate relative risks (RRs) and 95 % confidence intervals (CIs).

Results

We found no association between plasma calculated free 25(OH)D and risk of breast cancer overall (highest vs. lowest quartile RR 1.21, 95 % CI 0.83–1.77, trend test p value = 0.50). No association was observed for plasma DBP as well (highest vs. lowest quartile RR 0.95, 95 % CI 0.67–1.36, trend test p value = 0.96). Results were similar by tumor hormone receptor status. Neither the total nor the calculated free 25(OH)D and breast cancer association substantially varied by plasma DBP levels.

Conclusions

Our study does not support an important role of either calculated circulating free 25(OH)D or circulating DBP levels in breast cancer risk among predominantly premenopausal women.
Literature
1.
go back to reference Lopes N, Paredes J, Costa JL, Ylstra B, Schmitt F (2012) Vitamin D and the mammary gland: a review on its role in normal development and breast cancer. Breast Cancer Res 14:211PubMedCentralPubMedCrossRef Lopes N, Paredes J, Costa JL, Ylstra B, Schmitt F (2012) Vitamin D and the mammary gland: a review on its role in normal development and breast cancer. Breast Cancer Res 14:211PubMedCentralPubMedCrossRef
2.
go back to reference Zinser G, Packman K, Welsh J (2002) Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development 129:3067–3076PubMed Zinser G, Packman K, Welsh J (2002) Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development 129:3067–3076PubMed
3.
go back to reference Zerwekh JE (2008) Blood biomarkers of vitamin D status. Am J Clin Nutr 87:1087S–1091SPubMed Zerwekh JE (2008) Blood biomarkers of vitamin D status. Am J Clin Nutr 87:1087S–1091SPubMed
4.
go back to reference Bertone-Johnson ER, Chen WY, Holick MF et al (2005) Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14:1991–1997PubMedCrossRef Bertone-Johnson ER, Chen WY, Holick MF et al (2005) Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14:1991–1997PubMedCrossRef
5.
go back to reference Chlebowski RT, Johnson KC, Kooperberg C et al (2008) Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100:1581–1591PubMedCentralPubMedCrossRef Chlebowski RT, Johnson KC, Kooperberg C et al (2008) Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100:1581–1591PubMedCentralPubMedCrossRef
6.
go back to reference Freedman DM, Chang SC, Falk RT et al (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 17:889–894PubMedCentralPubMedCrossRef Freedman DM, Chang SC, Falk RT et al (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 17:889–894PubMedCentralPubMedCrossRef
7.
go back to reference McCullough ML, Stevens VL, Patel R et al (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:R64PubMedCentralPubMedCrossRef McCullough ML, Stevens VL, Patel R et al (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:R64PubMedCentralPubMedCrossRef
8.
go back to reference Rejnmark L, Tietze A, Vestergaard P et al (2009) Reduced prediagnostic 25-hydroxyvitamin D levels in women with breast cancer: a nested case–control study. Cancer Epidemiol Biomarkers Prev 18:2655–2660PubMedCrossRef Rejnmark L, Tietze A, Vestergaard P et al (2009) Reduced prediagnostic 25-hydroxyvitamin D levels in women with breast cancer: a nested case–control study. Cancer Epidemiol Biomarkers Prev 18:2655–2660PubMedCrossRef
9.
go back to reference Agborsangaya CB, Surcel HM, Toriola AT et al (2010) Serum 25-hydroxyvitamin D at pregnancy and risk of breast cancer in a prospective study. Eur J Cancer 46:467–470PubMedCrossRef Agborsangaya CB, Surcel HM, Toriola AT et al (2010) Serum 25-hydroxyvitamin D at pregnancy and risk of breast cancer in a prospective study. Eur J Cancer 46:467–470PubMedCrossRef
10.
go back to reference Almquist M, Bondeson AG, Bondeson L, Malm J, Manjer J (2010) Serum levels of vitamin D, PTH and calcium and breast cancer risk—a prospective nested case–control study. Int J Cancer 127:2159–2168PubMedCrossRef Almquist M, Bondeson AG, Bondeson L, Malm J, Manjer J (2010) Serum levels of vitamin D, PTH and calcium and breast cancer risk—a prospective nested case–control study. Int J Cancer 127:2159–2168PubMedCrossRef
11.
go back to reference Engel P, Fagherazzi G, Boutten A et al (2010) Serum 25(OH) vitamin D and risk of breast cancer: a nested case–control study from the French E3 N cohort. Cancer Epidemiol Biomarkers Prev 19:2341–2350PubMedCrossRef Engel P, Fagherazzi G, Boutten A et al (2010) Serum 25(OH) vitamin D and risk of breast cancer: a nested case–control study from the French E3 N cohort. Cancer Epidemiol Biomarkers Prev 19:2341–2350PubMedCrossRef
12.
go back to reference Eliassen AH, Spiegelman D, Hollis BW, Horst RL, Willett WC, Hankinson SE (2011) Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses’ Health Study II. Breast Cancer Res 13:R50PubMedCentralPubMedCrossRef Eliassen AH, Spiegelman D, Hollis BW, Horst RL, Willett WC, Hankinson SE (2011) Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses’ Health Study II. Breast Cancer Res 13:R50PubMedCentralPubMedCrossRef
13.
go back to reference Kuhn T, Kaaks R, Becker S et al (2013) Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: a nested case–control study. Int J Cancer 133:1689–1700PubMedCrossRef Kuhn T, Kaaks R, Becker S et al (2013) Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: a nested case–control study. Int J Cancer 133:1689–1700PubMedCrossRef
14.
go back to reference Scarmo S, Afanasyeva Y, Lenner P et al (2013) Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case–control study. Breast Cancer Res 15:R15PubMedCentralPubMedCrossRef Scarmo S, Afanasyeva Y, Lenner P et al (2013) Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case–control study. Breast Cancer Res 15:R15PubMedCentralPubMedCrossRef
15.
go back to reference Mohr SB, Gorham ED, Alcaraz JE et al (2013) Serum 25-hydroxyvitamin D and breast cancer in the military: a case–control study utilizing pre-diagnostic serum. Cancer Causes Control 24:495–504PubMedCrossRef Mohr SB, Gorham ED, Alcaraz JE et al (2013) Serum 25-hydroxyvitamin D and breast cancer in the military: a case–control study utilizing pre-diagnostic serum. Cancer Causes Control 24:495–504PubMedCrossRef
16.
go back to reference Mendel CM (1989) The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 10:232–274PubMedCrossRef Mendel CM (1989) The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 10:232–274PubMedCrossRef
17.
go back to reference Bikle DD, Siiteri PK, Ryzen E, Haddad JG (1985) Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab 61:969–975PubMedCrossRef Bikle DD, Siiteri PK, Ryzen E, Haddad JG (1985) Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab 61:969–975PubMedCrossRef
18.
go back to reference Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG (1986) Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab 63:954–959PubMedCrossRef Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG (1986) Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab 63:954–959PubMedCrossRef
19.
go back to reference Powe CE, Ricciardi C, Berg AH et al (2011) Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. J Bone Miner Res 26:1609–1616PubMedCentralPubMedCrossRef Powe CE, Ricciardi C, Berg AH et al (2011) Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. J Bone Miner Res 26:1609–1616PubMedCentralPubMedCrossRef
20.
go back to reference Bhan I, Powe CE, Berg AH et al (2012) Bioavailable vitamin D is more tightly linked to mineral metabolism than total vitamin D in incident hemodialysis patients. Kidney Int 82:84–89PubMedCentralPubMedCrossRef Bhan I, Powe CE, Berg AH et al (2012) Bioavailable vitamin D is more tightly linked to mineral metabolism than total vitamin D in incident hemodialysis patients. Kidney Int 82:84–89PubMedCentralPubMedCrossRef
21.
go back to reference White P, Cooke N (2000) The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 11:320–327PubMedCrossRef White P, Cooke N (2000) The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 11:320–327PubMedCrossRef
22.
go back to reference Safadi FF, Thornton P, Magiera H et al (1999) Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest 103:239–251PubMedCentralPubMedCrossRef Safadi FF, Thornton P, Magiera H et al (1999) Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest 103:239–251PubMedCentralPubMedCrossRef
23.
go back to reference Mondul AM, Weinstein SJ, Virtamo J, Albanes D (2012) Influence of vitamin D binding protein on the association between circulating vitamin D and risk of bladder cancer. Br J Cancer 107:1589–1594PubMedCentralPubMedCrossRef Mondul AM, Weinstein SJ, Virtamo J, Albanes D (2012) Influence of vitamin D binding protein on the association between circulating vitamin D and risk of bladder cancer. Br J Cancer 107:1589–1594PubMedCentralPubMedCrossRef
24.
go back to reference Weinstein SJ, Stolzenberg-Solomon RZ, Kopp W, Rager H, Virtamo J, Albanes D (2012) Impact of circulating vitamin D binding protein levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk: a nested case–control study. Cancer Res 72:1190–1198PubMedCentralPubMedCrossRef Weinstein SJ, Stolzenberg-Solomon RZ, Kopp W, Rager H, Virtamo J, Albanes D (2012) Impact of circulating vitamin D binding protein levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk: a nested case–control study. Cancer Res 72:1190–1198PubMedCentralPubMedCrossRef
25.
go back to reference Weinstein SJ, Mondul AM, Kopp W, Rager H, Virtamo J, Albanes D (2013) Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of prostate cancer. Int J Cancer 132:2940–2947PubMedCrossRef Weinstein SJ, Mondul AM, Kopp W, Rager H, Virtamo J, Albanes D (2013) Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of prostate cancer. Int J Cancer 132:2940–2947PubMedCrossRef
26.
go back to reference Tworoger SS, Sluss P, Hankinson SE (2006) Association between plasma prolactin concentrations and risk of breast cancer among predominately premenopausal women. Cancer Res 66:2476–2482PubMedCrossRef Tworoger SS, Sluss P, Hankinson SE (2006) Association between plasma prolactin concentrations and risk of breast cancer among predominately premenopausal women. Cancer Res 66:2476–2482PubMedCrossRef
27.
go back to reference Rosner B (1983) Percentage points for a generalized ESD many-outlier procedure. Technometrics 25:165–172CrossRef Rosner B (1983) Percentage points for a generalized ESD many-outlier procedure. Technometrics 25:165–172CrossRef
28.
go back to reference Manolio TA, Burke GL, Psaty BM et al (1995) Black-white differences in subclinical cardiovascular disease among older adults: the Cardiovascular Health Study. CHS Collaborative Research Group. J Clin Epidemiol 48:1141–1152PubMedCrossRef Manolio TA, Burke GL, Psaty BM et al (1995) Black-white differences in subclinical cardiovascular disease among older adults: the Cardiovascular Health Study. CHS Collaborative Research Group. J Clin Epidemiol 48:1141–1152PubMedCrossRef
29.
go back to reference Bouillon R, Van Assche FA, Van Baelen H, Heyns W, De Moor P (1981) Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3. Significance of the free 1,25-dihydroxyvitamin D3 concentration. J Clin Invest 67:589–596PubMedCentralPubMedCrossRef Bouillon R, Van Assche FA, Van Baelen H, Heyns W, De Moor P (1981) Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3. Significance of the free 1,25-dihydroxyvitamin D3 concentration. J Clin Invest 67:589–596PubMedCentralPubMedCrossRef
30.
31.
go back to reference Govindarajulu US, Spiegelman D, Thurston SW, Ganguli B, Eisen EA (2007) Comparing smoothing techniques in Cox models for exposure-response relationships. Stat Med 26:3735–3752PubMedCrossRef Govindarajulu US, Spiegelman D, Thurston SW, Ganguli B, Eisen EA (2007) Comparing smoothing techniques in Cox models for exposure-response relationships. Stat Med 26:3735–3752PubMedCrossRef
32.
go back to reference Marshall RJ, Chisholm EM (1985) Hypothesis testing in the polychotomous logistic model with an application to detecting gastrointestinal cancer. Stat Med 4:337–344PubMedCrossRef Marshall RJ, Chisholm EM (1985) Hypothesis testing in the polychotomous logistic model with an application to detecting gastrointestinal cancer. Stat Med 4:337–344PubMedCrossRef
33.
go back to reference Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL (2013) Plasma vitamin D levels, menopause, and risk of breast cancer: dose–response meta-analysis of prospective studies. Medicine. 92:123–131PubMedCrossRef Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL (2013) Plasma vitamin D levels, menopause, and risk of breast cancer: dose–response meta-analysis of prospective studies. Medicine. 92:123–131PubMedCrossRef
34.
go back to reference Mondul AM, Weinstein SJ, Moy KA, Mannisto S, Albanes D (2013) Vitamin D binding protein, circulating vitamin D, and risk of renal cell carcinoma. Int J Cancer. doi:10.1002/ijc.28596 PubMed Mondul AM, Weinstein SJ, Moy KA, Mannisto S, Albanes D (2013) Vitamin D binding protein, circulating vitamin D, and risk of renal cell carcinoma. Int J Cancer. doi:10.​1002/​ijc.​28596 PubMed
35.
go back to reference Mondul AM, Weinstein SJ, Horst RL, Purdue M, Albanes D (2012) Serum vitamin D and risk of bladder cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial. Cancer Epidemiol Biomarkers Prev 21:1222–1225PubMedCentralPubMedCrossRef Mondul AM, Weinstein SJ, Horst RL, Purdue M, Albanes D (2012) Serum vitamin D and risk of bladder cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial. Cancer Epidemiol Biomarkers Prev 21:1222–1225PubMedCentralPubMedCrossRef
36.
go back to reference Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG, Stampfer MJ (1996) Circulating vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer Epidemiol Biomarkers Prev 5:121–126PubMed Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG, Stampfer MJ (1996) Circulating vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer Epidemiol Biomarkers Prev 5:121–126PubMed
37.
go back to reference Corder EH, Friedman GD, Vogelman JH, Orentreich N (1995) Seasonal variation in vitamin D, vitamin D-binding protein, and dehydroepiandrosterone: risk of prostate cancer in black and white men. Cancer Epidemiol Biomarkers Prev 4:655–659PubMed Corder EH, Friedman GD, Vogelman JH, Orentreich N (1995) Seasonal variation in vitamin D, vitamin D-binding protein, and dehydroepiandrosterone: risk of prostate cancer in black and white men. Cancer Epidemiol Biomarkers Prev 4:655–659PubMed
38.
go back to reference Willnow TE, Nykjaer A (2010) Cellular uptake of steroid carrier proteins–mechanisms and implications. Mol Cell Endocrinol 316:93–102PubMedCrossRef Willnow TE, Nykjaer A (2010) Cellular uptake of steroid carrier proteins–mechanisms and implications. Mol Cell Endocrinol 316:93–102PubMedCrossRef
39.
go back to reference Rowling MJ, Kemmis CM, Taffany DA, Welsh J (2006) Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 136:2754–2759PubMedCentralPubMed Rowling MJ, Kemmis CM, Taffany DA, Welsh J (2006) Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 136:2754–2759PubMedCentralPubMed
40.
go back to reference Chlon TM, Taffany DA, Welsh J, Rowling MJ (2008) Retinoids modulate expression of the endocytic partners megalin, cubilin, and disabled-2 and uptake of vitamin D-binding protein in human mammary cells. J Nutr 138:1323–1328PubMedCentralPubMed Chlon TM, Taffany DA, Welsh J, Rowling MJ (2008) Retinoids modulate expression of the endocytic partners megalin, cubilin, and disabled-2 and uptake of vitamin D-binding protein in human mammary cells. J Nutr 138:1323–1328PubMedCentralPubMed
41.
go back to reference Kotsopoulos J, Tworoger SS, Campos H et al (2010) Reproducibility of plasma and urine biomarkers among premenopausal and postmenopausal women from the Nurses’ Health Studies. Cancer Epidemiol Biomarkers Prev 19:938–946PubMedCentralPubMedCrossRef Kotsopoulos J, Tworoger SS, Campos H et al (2010) Reproducibility of plasma and urine biomarkers among premenopausal and postmenopausal women from the Nurses’ Health Studies. Cancer Epidemiol Biomarkers Prev 19:938–946PubMedCentralPubMedCrossRef
Metadata
Title
Plasma free 25-hydroxyvitamin D, vitamin D binding protein, and risk of breast cancer in the Nurses’ Health Study II
Authors
Jun Wang
A. Heather Eliassen
Donna Spiegelman
Walter C. Willett
Susan E. Hankinson
Publication date
01-07-2014
Publisher
Springer International Publishing
Published in
Cancer Causes & Control / Issue 7/2014
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI
https://doi.org/10.1007/s10552-014-0383-5

Other articles of this Issue 7/2014

Cancer Causes & Control 7/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine