Prediagnostic 25-Hydroxyvitamin D Concentrations in Relation to Tumor Molecular Alterations and Risk of Breast Cancer Recurrence
- 31 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Epidemiology, Biomarkers & Prevention
- Vol. 29 (6), 1253-1263
- https://doi.org/10.1158/1055-9965.EPI-19-1217
Abstract
Background: Although vitamin D inhibits breast tumor growth in experimental settings, the findings from populationbased studies remain inconclusive. Our goals were to investigate the association between prediagnostic plasma 25-hydroxy-vitamin D [25(OH)D] concentration and breast cancer recurrence in prospective epidemiologic studies and to explore the molecular underpinnings linking 25(OH)D to slower progression of breast cancer in the Nurses' Health Studies (NHS, N = 659). Methods: Plasma 25(OH)D was measured with a high-affinity protein-binding assay and a radioimmunoassay. We profiled transcriptome-wide gene expression in breast tumors using microarrays. Hazard ratios (HR) of breast cancer recurrence were estimated from covariate-adjusted Cox regressions. We examined differential gene expression in association with 25 (OH)D and employed pathway analysis. We derived a gene expression score for 25(OH)D, and assessed associations between the score and cancer recurrence. Results: Although 25(OH)D was not associated with breast cancer recurrence overall [HR = 0.97; 95% confidence interval (CI), 0.88-1.08], the association varied by estrogen-receptor (ER) status (P-interaction = 0.005). Importantly, among ER-positive stage I to III cancers, every 5 ng/mL increase in 25(OH)D was associated with a 13% lower risk of recurrence (HR = 0.87; 95% CI, 0.76-0.99). A null association was observed for ER-negative cancers (HR = 1.07; 95% CI, 0.91-1.27). Pathway analysis identified multiple gene sets that were significantly (FDR < 5%) downregulated in ER-positive tumors of women with high 25(OH)D (>= 30 ng/mL), compared with those with low levels (<30 ng/mL). These gene sets are primarily involved in tumor proliferation, migration, and inflammation. 25(OH) D score derived from these gene sets was marginally associated with reduced risk of recurrence in ER-positive diseases (HR = 0.77; 95% CI, 0.59-1.01) in the NHS studies; however no association was noted in METABRIC, suggesting that further refinement is need to improve the generalizability of the score. Conclusions: Our findings support an intriguing line of research for studies to better understand the mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype. Impact: Vitamin D may present a personal-level secondaryprevention strategy for ER-positive breast cancer.Funding Information
- NIH
- NCI (CA186107)
- National Institute of Health Epidemiology Education Training Great (T32 CA09001)
- Susan G. Komen for the Cure
- ® (IIR13264020, SAC110014)
- Prevent Cancer Foundation
This publication has 51 references indexed in Scilit:
- Vitamin D receptor as a master regulator of the c-MYC/MXD1 networkProceedings of the National Academy of Sciences of the United States of America, 2012
- Camera: a competitive gene set test accounting for inter-gene correlationNucleic Acids Research, 2012
- The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroupsNature, 2012
- Body Size in Early Life and Adult Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3American Journal of Epidemiology, 2011
- Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses' Health Study IIBreast Cancer Research, 2011
- Reproducibility of Plasma, Red Blood Cell, and Urine Biomarkers among Premenopausal and Postmenopausal Women from the Nurses' Health StudiesCancer Epidemiology, Biomarkers & Prevention, 2010
- Prognostic Effects of 25-Hydroxyvitamin D Levels in Early Breast CancerJournal of Clinical Oncology, 2009
- Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable AnalysisPLoS Genetics, 2007
- Vitamin D signalling pathways in cancer: potential for anticancer therapeuticsNature Reviews Cancer, 2007
- Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray ExperimentsStatistical Applications in Genetics and Molecular Biology, 2004