Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.

2002 ◽  
pp. 45-59 ◽  
Author(s):  
K W Colston ◽  
C M√∏rk Hansen
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Bone Mineralization ◽  
Active Form ◽  
Cell Types ◽  
Cell Cycle Regulators ◽  
Dihydroxyvitamin D ◽  
Cell Growth And Differentiation ◽  
Regulatory Effects ◽  
Apoptotic Effects

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.

scholarly journals Vitamin D3and the immune system: maintaining the balance in health and disease

2007 ◽  
Vol 20 (1) ◽  
pp. 106-118 ◽  
Author(s):  
Femke Baeke ◽  
Evelyne Van Etten ◽  
Lut Overbergh ◽  
Chantal Mathieu
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
Immune System ◽  
Animal Models ◽  
Autoimmune Diseases ◽  
Active Form ◽  
Epidemiological Data ◽  
Cell Types ◽  
Dihydroxyvitamin D

1,25-Dihydroxyvitamin D3(1,25(OH)2D3), the active form of vitamin D3, is a central player in Ca and bone metabolism. More recently, important immunomodulatory effects have been attributed to this hormone. By binding to its receptor, the vitamin D receptor, 1,25(OH)2D3regulates the expression of various genes and consequently affects the behaviour of different cell types within the immune system. 1,25(OH)2D3can potently inhibit pathogenic T cells and gives rise to elevated numbers of regulatory T cells via the induction of tolerogenic dendritic cells. These immunomodulatory activities of 1,25(OH)2D3have also been proven usefulin vivo: administration of 1,25(OH)2D3in several animal models can prevent or cure different autoimmune diseases and graft rejection. To overcome the dose-limiting side effects of 1,25(OH)2D3on Ca and bone, less calcaemic structural analogues (alone or in combination with synergistically acting drugs or bone-resorption inhibitors) have been successfully used in animal models. Furthermore, as 1,25(OH)2D3also contributes to host defence against infectious agents by the induction of antimicrobial responses, this molecule might provide a new strategy to deal with drug-resistant infections. According to the pleiotropic effects of 1,25(OH)2D3in the immune system, increasing epidemiological data underline the importance of adequate vitamin D intakes in reducing the risk of several autoimmune diseases and infections such as tuberculosis.

scholarly journals Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

2016 ◽  
Vol 37 (5) ◽  
pp. 521-547 ◽  
Author(s):  
Peter J. Tebben ◽  
Ravinder J. Singh ◽  
Rajiv Kumar
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Elevated Serum ◽  
Diagnosis And Treatment ◽  
Vitamin D Metabolites ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Stone Formers ◽  
25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

scholarly journals High concentration calcitriol induces endoplasmic reticulum stress related gene profile in breast cancer cells

2017 ◽  
Vol 95 (2) ◽  
pp. 289-294 ◽  
Author(s):  
Ali Burak Ozkaya ◽  
Handan Ak ◽  
Hikmet Hakan Aydin
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Survival Function ◽  
Active Form ◽  
Breast Cancer Cell Lines ◽  
Transcriptomic Profile

Calcitriol, the active form of vitamin D, is known for its anticancer properties including induction of apoptosis as well as the inhibition of angiogenesis and metastasis. Understanding the mechanisms of action for calcitriol will help with the development of novel treatment strategies. Since vitamin D exerts its cellular actions via binding to its receptor and by altering expressions of a set of genes, we aimed to evaluate the effect of calcitriol on transcriptomic profile of breast cancer cells. We previously demonstrated that calcitriol alters endoplasmic reticulum (ER) stress markers, therefore in this study we have focused on ER-stress-related genes to reveal calcitriols action on these genes in particular. We have treated breast cancer cell lines MCF-7 and MDA-MB-231 with previously determined IC50 concentrations of calcitriol and evaluated the transcriptomic alterations via microarray. During analysis, only genes altered by at least 2-fold with a P value < 0.05 were taken into consideration. Our findings revealed an ER-stress-associated transcriptomic profile induced by calcitriol. Induced genes include genes with a pro-survival function (NUPR1, DNAJB9, HMOX1, LCN2, and LAMP3) and with a pro-death function (CHOP (DDIT3), DDIT4, NDGR1, NOXA, and CLGN). These results suggest that calcitriol induces an ER-stress-like response inducing both pro-survival and pro-death transcripts in the process.

scholarly journals Regulation and Function of the FGF23/Klotho Endocrine Pathways

2012 ◽  
Vol 92 (1) ◽  
pp. 131-155 ◽  
Author(s):  
Aline Martin ◽  
Valentin David ◽  
L. Darryl Quarles
Keyword(s):  
Vitamin D ◽  
Intestinal Absorption ◽  
Mineral Metabolism ◽  
Bone Mineralization ◽  
Phosphate Homeostasis ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Tubular Phosphate Reabsorption ◽  
Renal Tubular ◽  
And Function

Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

scholarly journals Is the Vitamin D Receptor Found in Muscle?

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 354-363 ◽  
Author(s):  
Yongji Wang ◽  
Hector F. DeLuca
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Bone Mineralization ◽  
Active Form ◽  
Dihydroxyvitamin D3 ◽  
Neuromuscular Activity ◽  
Immunohistochemical Assay ◽  
Underlying Mechanisms ◽  
Positive Results ◽  
Phosphorus Levels

Abstract The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is critical for the regulation of serum calcium and phosphorus levels that in turn support bone mineralization and neuromuscular activity. It is well known that vitamin D deficiency causes rachitic/osteomalacic myopathy and cardiac disorder and the provision of vitamin D can reverse the symptoms. However, the underlying mechanisms remain unclear. The question of whether the vitamin D receptor is found in muscle has been debated but not settled. We recently studied all available antibodies against the vitamin D receptor and found that most antibodies used detect proteins other than the vitamin D receptor, and therefore, the utility of these antibodies may generate the false-positive results. Using antibodies that do not detect proteins in tissues from vitamin D receptor null mice, we have developed a specific and sensitive immunohistochemical assay. The results from this investigation show that the vitamin D receptor is undetectable in skeletal, cardiac, and smooth muscle, suggesting that the function of vitamin D on muscle is either of an indirect nature or does not involve the known receptor.

scholarly journals Vitamin D receptor as a target for breast cancer therapy

2017 ◽  
Vol 24 (4) ◽  
pp. 181-195 ◽  
Author(s):  
Alyson Murray ◽  
Stephen F Madden ◽  
Naoise C Synnott ◽  
Rut Klinger ◽  
Darran O'Connor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Active Form ◽  
Cancer Cell Line ◽  
Breast Cancer Cell Lines ◽  
Negative Cell ◽  
Anti Cancer

Considerable epidemiological evidence suggests that high levels of circulating vitamin D (VD) are associated with a decreased incidence and increased survival from cancer, i.e., VD may possess anti-cancer properties. The aim of this investigation was therefore to investigate the anti-cancer potential of a low calcaemic vitamin D analogue, i.e., inecalcitol and compare it with the active form of vitamin D, i.e., calcitriol, in a panel of breast cancer cell lines (n = 15). Using the MTT assay, IC50concentrations for response to calcitriol varied from 0.12 µM to >20 µM, whereas those for inecalcitol were significantly lower, ranging from 2.5 nM to 63 nM (P = 0.001). Sensitivity to calcitriol and inecalcitol was higher in VD receptor (VDR)-positive compared to VDR-negative cell lines (P = 0.0007 and 0.0080, respectively) and in ER-positive compared to ER-negative cell lines (P = 0.043 and 0.005, respectively). Using RNA-seq analysis, substantial but not complete overlap was found between genes differentially regulated by calcitriol and inecalcitol. In particular, significantly enriched gene ontology terms such as cell surface signalling and cell communication were found after treatment with inecalcitol but not with calcitriol. In contrast, ossification and bone morphogenesis were found significantly enriched after treatment with calcitriol but not with inecalcitol. Our preclinical results suggest that calcitriol and inecalcitol can inhibit breast cancer cell line growth, especially in cells expressing ER and VDR. As inecalcitol is significantly more potent than calcitriol and has low calcaemic potential, it should be further investigated for the treatment of breast cancer.

Correlation between vitamin D deficiency and metastatic breast carcinoma in a predominantly Hispanic population: A retrospective study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12553-e12553
Author(s):  
Saurabh Deepak Chitnis ◽  
Andrea M. Popescu-Martinez
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Metastatic Breast Cancer ◽  
Relative Risk ◽  
Vitamin D Deficiency ◽  
Active Form ◽  
Metastatic Breast ◽  
Breast Cancer Cell Lines ◽  
Vitamin D Levels

e12553 Background: There have been numerous studies conducted linking Vitamin D deficiency to various cancers, including cancers of the breast. Studies associating Vitamin D deficiency and Breast cancer have shown mixed results in patients with no clear consensus. Recently published in vitro studies have shown that the active form of Vitamin D can inhibit the metastatic capability of breast cancer cell lines to bone. Based on this we aimed to elucidate whether there exists any correlation between Vitamin D deficiency at diagnosis and Metastatic breast cancer. Methods: Retrospective analysis of the EMR for women diagnosed with breast cancer and enrolled in Oncology database seen at NYMC-Metropolitan Hospital Center from 2010-2016 was done. Patients were grouped into either breast cancer with metastases or without metastases and their Vitamin D levels at diagnosis were reviewed. Patients with 25- Hydroxy Vitamin D levels measured within one year of diagnosis of breast cancer were included for the study. Study was planned from 2010-2016 specifically as Vitamin D levels for patients were not monitored as frequently prior to 2010. Results: From total of 102 patients who started follow up with Oncology clinic during the study time period, 2 were referred to our center for further management with diagnosis made prior to 2010 and were not included in the study. Out of the 100 patients considered, 58 patients had Vitamin D levels measured within a year of diagnosis of breast cancer and were included in the study. 70% of the population was Latino/Hispanic. The table represents the results of the study. Odds ratio for a patient with Vit D deficiency to develop metastatic breast cancer was 0.92 and relative risk was calculated to be 0.93. Conclusions: Based on above results, the outcome was similar in both groups. The odd’s ratio and the relative risk imply that there was no difference evidenced between both groups. These findings signify that there was no direct correlation between Metastatic breast cancer and Vitamin D deficiency at time of diagnosis in the population seen at our center. [Table: see text]

scholarly journals Vitamin D Promotes MSC Osteogenic Differentiation Stimulating Cell Adhesion and αVβ3 Expression

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Francesca Posa ◽  
Adriana Di Benedetto ◽  
Elisabetta A. Cavalcanti-Adam ◽  
Graziana Colaianni ◽  
Chiara Porro ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cell Adhesion ◽  
Osteogenic Differentiation ◽  
Matrix Protein ◽  
Active Form ◽  
Focal Adhesions ◽  
Supporting Cell ◽  
Integrin Expression ◽  
Dihydroxyvitamin D ◽  
Cell Commitment

Vitamin D (Vit D) by means of its biological active form, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), has a protective effect on the skeleton by acting on calcium homeostasis and bone formation. Furthermore, Vit D has a direct effect on mesenchymal stem cells (MSCs) in stimulating their osteogenic differentiation. In this work, we present for the first time the effect of 1,25(OH)2D3 on MSC adhesion. Considering that cell adhesion to the substrate is fundamental for cell commitment and differentiation, we focused on the expression of αVβ3 integrin, which has a key role in the commitment of MSCs to the osteoblastic lineage. Our data indicate that Vit D increases αVβ3 integrin expression inducing the formation of focal adhesions (FAs). Moreover, we assayed MSC commitment in the presence of the extracellular matrix (ECM) glycoprotein fibronectin (FN), which is able to favor cell adhesion on surfaces and also to induce osteopontin (OPN) expression: this suggests that Vit D and FN synergize in supporting cell adhesion. Taken together, our findings provide evidence that Vit D can promote osteogenic differentiation of MSCs through the modulation of αVβ3 integrin expression and its subcellular organization, thus favoring binding with the matrix protein (FN).

scholarly journals Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements

2013 ◽  
Vol 20 (4) ◽  
pp. 565-577 ◽  
Author(s):  
Srilatha Swami ◽  
Aruna V Krishnan ◽  
Lihong Peng ◽  
Johan Lundqvist ◽  
David Feldman
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Estrogen Receptor ◽  
Promoter Sequence ◽  
Estrogen Receptor Α ◽  
Mobility Shift ◽  
Response Elements ◽  
Dihydroxyvitamin D ◽  
Mobility Shift Assay ◽  
Estrogen Receptor Promoter

Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts its anti-proliferative activity in breast cancer (BCa) cells by multiple mechanisms including the downregulation of the expression of estrogen receptor α (ER). We analyzed an ∼3.5 kb ER promoter sequence and demonstrated the presence of two potential negative vitamin D response elements (nVDREs), a newly identified putative nVDRE upstream at −2488 to −2473 bp (distal nVDRE) and a previously published sequence (proximal nVDRE) at −94 to −70 bp proximal to the P1 start site. Transactivation analysis using ER promoter deletion constructs and heterologous promoter–reporter constructs revealed that both nVDREs functioned to mediate calcitriol transrepression. In the electrophoretic mobility shift assay, the vitamin D receptor (VDR) showed strong binding to both nVDREs in the presence of calcitriol, and the chromatin immunoprecipitation assay demonstrated the recruitment of the VDR to the distal nVDRE site. Mutations in the 5′ hexameric DNA sequence of the distal nVDRE resulted in the loss of calcitriol-mediated transrepression and the inhibition of protein–DNA complex formation, demonstrating the importance of these nucleotides in VDR DNA binding and transrepression. A putative nuclear factor-Y (NFY) binding site, identified within the distal nVDRE, led to the findings that NFY bound to the distal nVDRE site interfered with the binding of the VDR at the site and reduced calcitriol-mediated transrepression. In conclusion, the ER promoter region contains two negative VDREs that act in concert to bind to the VDR and both nVDREs are required for the maximal inhibition of ER expression by calcitriol. The suppression of ER expression and estrogen-mediated signaling by calcitriol in BCa cells suggests that vitamin D may be useful in the treatment of ER+ BCa.

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