Prognostic role of vitamin D receptor in breast cancer: a systematic review and meta-analysis

Abstract

Background A higher vitamin D intake improves the prognosis of early stage breast cancer (BC) patients. We hypothesized that vitamin D intake should refer to vitamin D receptor (VDR) expression. In order to prove this hypothesis, we first intend to evaluate the correlation between VDR expression and prognosis of BC patients using meta-analysis. Methods Literatures from PubMed, Embase, and the Cochrane Library (last update by May 20, 2020) were retrieved to find studies assessing the prognostic role of VDR in BC. The hazard ratios (HRs) for patients’ survival were extracted for pooled analyses. Subgroup analysis, sensitivity analysis and meta-regression were performed to explore the sources of heterogeneity. Results Seven articles containing eight studies with 2503 patients were enrolled. The results from the pooled analyses showed that the VDR expression generally had no relationship with BC patients’ overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and progression-free survival (PFS) (P > 0.05). Because only the number of studies exploring the relationship between VDR expression and OS is greater than five and there is heterogeneity, we explored the sources of heterogeneity of these studies. Subgroup analyses showed that the VDR expression in the nucleus had no relationship with OS, but high total VDR expression in the nucleus and cytoplasm was related to a better OS (pooled HR = 0.41; 95% CI = 0.18–0.95; P = 0.038). In addition, in subgroup of studies using cut-off values other than ‘immunoreactive score (IRS)>5’ and ‘IRS > 25′, high VDR expression was associated with a better OS (pooled HR = 0.47; 95% CI = 0.30–0.74; P = 0.001). Sensitivity analysis showed that the result pattern was not obviously affected by any single study. Meta-regression showed that the source of heterogeneity was not country (P = 0.657), pathological type (P = 0.614), molecular type (P = 0.423), staining location (P = 0.481), or cut-off value (P = 0.509). Conclusions The protein expression level of VDR in entire BC cells evaluated by immunohistochemistry is related to the OS of BC patients. It is expected that a more individualized vitamin D intake and a more accurate prognosis assessment can be recommended for BC patients based on the VDR expression. Of course, more preclinical and clinical studies are needed.

Is Vitamin D Deficiency Related to Increased Cancer Risk in Patients with Type 2 Diabetes Mellitus?

“…Interestingly, women with breast cancer with 25(OH)D level ≥ 99 nmol/L also had worse PFS and OS [ 237 ]. Of note, Xu et al showed that the level of VDR protein expression in neoplastic cells in patients with breast cancer was related to OS, therefore, they recommned individualized vitamin D intake to assess breast cancer prognosis [ 238 ]. In case of lung cancer, Huang et al conducted a meta-analysis of eight cohort studies to evaluate the correlation between serum 25(OH)D level and OS.…”

Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

“…The relationship between Vitamin D and breast cancer remains controversial. A recent meta-analysis demonstrated that while there is no relationship between nuclear VDR (NR1I1) expression and overall survival in patients with breast cancer, high total nuclear and cytoplasmic VDR expression was associated with improved survival outcomes [ 167 ]. Both the VDR and vitamin D 1-hydroxylase, the enzyme that generates the active Vitamin D3 ligand 1,25-dihydroxycholecalciferol, are expressed in the human breast.…”

“…Additionally, VDR expression correlates with the expression of ER. Interest has been provoked by growing evidence suggesting that adequate Vitamin D levels and intake inversely correlate with breast cancer risk [168][169][170], and that low levels of vitamin D are associated with an increased risk of recurrence or death in breast cancer patients [167,171]. This is arguably enough evidence to suggest that early breast cancer patients should at least supplement vitamin D if found to be deficient.…”

Vitamin D and Breast Cancer: Mechanistic Update

“…However, one conclusion that can be made is that the majority of breast cancers express VDR protein at a moderate level, and a significant percentage show high VDR immunoreactivity. A recent meta-analysis of the published immunohistochemical data has supported the concept that higher VDR protein is beneficial for patient survival, (62) but this likely depends on disease stage/grade and subtype.…”