Tumor Expression of Vitamin D Receptor and Breast Cancer Histopathological Characteristics and Prognosis

Abstract

Purpose Our previous work has shown low serum 25-hydroxyvitamin D concentrations in association with aggressive breast cancer subtypes. Vitamin D receptor (VDR) is central for vitamin D-mediated transcription regulation. Few studies have examined breast VDR expression with tumor characteristics or patient survival. Experimental Design VDR expression in breast tumor tissue microarrays was determined by immunohistochemistry in 1,114 female patients as low, moderate and strong expression based on an immunoreactive score, and examined with histopathological tumor characteristics and survival outcomes including progression free survival, breast cancer specific survival, and overall survival. Results A majority (58%) of breast tumors showed moderate or strong VDR expression. VDR expression was inversely related to aggressive tumor characteristics, including large tumor size, hormonal receptor (HR) negativity, and triple-negative subtype (p<0.05). In addition, VDR expression was also inversely related to Ki-67 expression among patients older than 50 years. Nevertheless, VDR expression was not associated with any patient survival outcomes examined. Conclusions In a large patient population, VDR expression is inversely associated with more aggressive breast cancer, but not with breast cancer survival outcomes. The present findings of VDR expression are consistent with our previous results of circulating vitamin D biomarkers, which provide two converging lines of evidence supporting the putative benefits of vitamin D against aggressive breast cancer. Because of the observational nature of our analyses, future studies are warranted to establish the causality of the reported associations.

Function of the vitamin D endocrine system in mammary gland and breast cancer

“…An early study of 136 patients with primary breast cancer reported that women with VDR negative tumors relapsed significantly earlier than women with VDR positive tumors (22). In a more recent study of >1000 human breast cancers of mixed sub-types, Al-Azhri et al (23) reported that VDR expression was inversely related to tumor size, hormone receptor negativity and TNBC subtype. This is consistent with data showing that VDR protein expression declines in highly aggressive tumors (24; 25) and is deregulated by oncogenic transformation (26–28).…”

Vitamin D Receptor Polymorphism and Cancer: An Update

“…Increased expression of VDR has been found in breast cancer and inversely related to aggressive tumor characteristics, including large tumor size, hormonal receptor (HR) negativity, triplenegative subtype [estrogen-receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) negative], and expression of proliferative marker Ki-67 (23). Similarly, various casecontrol studies suggested that the association between VDR polymorphism and risk of breast cancer may depend on race and ethnicity.…”

Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization

“…Several studies have shown that the VDR is differentially expressed in benign and malignant breast tissue, suggesting a role for the VDR in transcriptional and cell-cycle regulation, as well as cell differentiation and apoptosis. (20)(21)(22)(23)(24) Thus, the degree of VDR expression in malignant tissues is inversely related to aggressive tumor characteristics, (25,26) ie, high expression levels are associated with slower cancer progression and longer survival. (15,20,27,28) In murine models of breast cancer, overexpression of the VDR reduces the incidence of pulmonary metastases (26) ; conversely, VDR ablation promotes primary tumor growth as well as lung and hepatic metastases.…”