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

Abstract

The nuclear receptor for 1α,25-dihydroxycholecalciferol (1,25D), the active form of vitamin D, has anti-tumor actions in many tissues. The vitamin D receptor (VDR) is expressed in normal mammary gland and in many human breast cancers suggesting it may represent an important tumor suppressor gene in this tissue. When activated by 1,25D, VDR modulates multiple cellular pathways including those related to energy metabolism, terminal differentiation and inflammation. There is compelling pre-clinical evidence that alterations in vitamin D status affect breast cancer development and progression, while clinical and epidemiological data are suggestive but not entirely consistent. The demonstration that breast cells express CYP27B1 (which converts the precursor vitamin D metabolite 25D to the active metabolite 1,25D) and CYP24A1 (which degrades both 25D and 1,25D) provides insight into the difficulties inherent in using dietary vitamin D, sun exposure and/or serum biomarkers of vitamin D status to predict disease outcomes. Emerging evidence suggests that the normally tight balance between CYP27B1 and CYP24A1 becomes deregulated during cancer development, leading to abrogation of the tumor suppressive effects triggered by VDR. Research aimed at understanding the mechanisms that govern uptake, storage, metabolism and actions of vitamin D steroids in normal and neoplastic breast tissue remain an urgent priority.

Vitamin D receptor expression in canine mammary gland and relationship with clinicopathological parameters and progesterone/oestrogen receptors

“…These facts suggest that the highest VDR expression occurs in well‐differentiated cells and its expression decreases in poorly differentiated cells. In human breast cancer, several authors have showed that VDR protein expression declines in highly aggressive tumours . Furthermore, the well‐differentiated ME cells appear to be the canine mammary cell type that exhibits greater VDR expression, pointing to the presence of ME cells with different phenotypic characteristics in malignant tumours as formerly reported in the canine and human species …”

“…This result suggests that VDR could represent an important tumour suppressor protein. In humans, several authors have demonstrated that the VDR protein is expressed in samples from normal breast tissues and also in breast cancer biopsy specimens, but detailed insight into its distribution, regulation and function are still emerging . There is discrepancy both in whether the VDR expression is greater in normal or tumour breast tissue, as in the percentage of carcinomas expressing VDR protein.…”

“…In human breast cancer research, the studies have failed to find consistent relationship between VDR expression and clinicopathological data, hormonal expression receptors, breast cancer risk or progression . It could be due to the heterogeneity of breast cancer and the complexity of the control of VDR, with environmental (hormones, ligands, cytokines), genetic and epigenetic factors interacting to potentially drive expression of distinct variants or isoforms . Given the importance of VDR in mediating the pro‐differentiation and anti‐tumour effects of vitamin D, elucidation of factors that regulate VDR in breast tissue should be a research priority …”

“…In human breast, VDR expression has been demonstrated in epithelial, stromal and immune cells by immunohistochemistry . Because the VDR is expressed in the mammary gland and vitamin D and its analogues have been shown to display anticarcinogenic properties, this hormone has emerged as a promising targeted therapy. Several studies in human breast based on the relationship among VDR expression and clinicopathological characteristics, prognosis and steroid hormone receptors expression have been carried out, but they have failed to find consistent results.…”

Changes in Circulating Levels of 25-hydroxyvitamin D3 in Breast Cancer Patients Receiving Chemotherapy

“…From a tumor biology point of view, removal of the tumor by surgical resection and chemotherapy may have also resulted in recovery of circulating 25(OH)D 3 levels. Previous studies suggested that regulation of the vitamin D pathway may be altered in breast cancer cells (39,40). For example, more stable CYP24 mRNA profiles, responsible for clearing of the active metabolite 1,25(OH) 2 D, were found in human breast cancer cells as compared to normal human mammary epithelial cells (41).…”