Vitamin D and breast cancer

In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early-stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results. Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention.     

Activation of inositol phospholipid signaling and Ca2+ efflux in human breast cancer cells by bombesin

Members of the bombesin-related family of peptides (BRPs) are mitogenic for a variety of cell types; however, a role for these peptides has not been previously described in human breast cancer. Early membrane receptor signal transduction mechanisms associated with bombesin action include phospholipase C-mediated inositol phospholipid hydrolysis and the elevation of cytosolic Ca2+ levels. We have investigated a potential role for BRPs in breast cancer by studying their effect on phospholipid hydrolysis, 45Ca2+ efflux, and cell growth in the human breast cancer cell line MCF-7. Bombesin stimulated a dose-dependent increase in the hydrolysis product inositol monophosphate during 1 h with a half-maximal effect around 1 nM. A transient increase in inositol trisphosphate in response to bombesin was also apparent at 2 min. Two distinct bombesin receptor antagonists inhibited this bombesin-induced phospholipid hydrolysis. Both bombesin- and gastrin-releasing peptide also stimulated a dose-related increase in inositol phosphate production in T47D cells, a different human breast cancer cell line. The efflux of 45Ca2+ from prelabeled MCF-7 cells was also stimulated by bombesin. This apparent cellular Ca2+ mobilization was partly dependent on extracellular Ca2+ and was inhibited by Ni2+. Despite this activation of putative mitogenic signaling pathways, bombesin had no effect on either proliferation or DNA synthesis in MCF-7 cells. These data implicate a functional role for BRPs in human breast cancer.     

维生素D及其受体与乳腺癌

维生素D(VitD)和维生素D受体(VDR)除了人们所熟知生理功能外,近些年来还发现与肿瘤之间有密切关系.约80%的乳腺癌表达VitDR,体内体外实验证明VitD可以抑制乳腺癌细胞增殖,诱导凋亡.VitD的类似物有望成为一种新型的抗癌药物.     

Vitamin D receptors in breast cancer cells

Summary 1,25-(OH)₂-Vitamin D₃, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)₂-vitamin D₃ has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)₂-vitamin D₃.VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10^–9 M 1,25-(OH)₂-vitamin D₃ (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)₂-vitamin D₃ at concentrations up to 10^–6 M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)₂-vitamin D₃.     

Vitamin D and breast cancer: Emerging concepts

The benefit of vitamin D in cancer prevention and to certain extent therapy has been well recognized. The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2 D3) is a natural ligand for vitamin D receptor (VDR). Since 1,25(OH)2D3 exerts toxic effects at a concentration that is beneficial, nearly 1500 analogs of vitamin D have been synthesized and evaluated for their efficacy in a variety of carcinogenesis and human cancer models both in vitro and in vivo. Among these only a handful of them have been approved for evaluation in clinical trials for leukemia, breast, prostate and colon cancers. The mechanism of vitamin D action is mediated by the nuclear VDR and the signaling cascade for its action is extensively reported. In this review we focus on the newer concepts for vitamin D action. These include (1) differential effects of vitamin D in maintaining cell proliferation when the cells are under stress but suppressing cell growth when the cells are transformed; (2) functional significance of VDR polymorphism in potential vitamin D responsiveness; (3) regulation of constitutive splicing of vitamin D target gene, CYP24a, by the hormone and its significance; and (4) regulation of microRNA by vitamin D in breast cancer. It is anticipated that the new work in these selective areas would expand the understanding of vitamin D in breast cancer prevention and therapy.     

Vitamin D and breast cancer: interpreting current evidence

Preclinical investigations and selected clinical observational studies support an association between higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk. However, the recently updated report from the Institute of Medicine concluded that, for cancer and vitamin D, the evidence was 'inconsistent and insufficient to inform nutritional requirements'. Against this background, reports examining vitamin D intake, 25-hydroxyvitamin D levels and breast cancer incidence and outcome were reviewed. Current evidence supports the pursuit of several research questions but not routine 25-hydroxyvitamin D monitoring and vitamin D supplementation to reduce breast cancer incidence or improve breast cancer outcome.     

Vitamin D receptor gene polymorphisms and breast cancer risk.

PURPOSE: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The actions of 1,25-dihydroxyvitamin D3 are mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in a United Kingdom Caucasian population. EXPERIMENTAL DESIGN: In a retrospective case-control study, female breast cancer patients (n = 398) and control women (n = 427) were recruited, and three VDR polymorphisms were determined. RESULTS: The 3' VDR polymorphisms BsmI and variable-length poly(adenylate) sequence were both significantly associated with breast cancer risk; odds ratios (adjusted for age menopausal status and hormone replacement therapy usage) for bb genotype versus BB genotype = 1.92 (95% confidence interval, 1.20-3.10; P < 0.01) and for LL versus SS = 1.94 (95% confidence interval, 1.20-3.14; P < 0.01). A 5' VDR gene variant, FokI, was not associated with breast cancer risk when analyzed in isolation (P > 0.05). However, FokI did modulate the increased risk associated with the bb/LL genotype such that possession of one or more F alleles together with the bb/LL genotype augmented breast cancer risk. Furthermore, the highest proportion of bb and FFLL/FfLL genotypes occurred in women with metastatic breast cancer. CONCLUSIONS: VDR polymorphisms are associated with breast cancer risk and may be associated with disease progression. Additional investigations into how different genotypes may affect the functional mechanisms of the VDR will provide a better strategy for identifying women at risk of breast cancer and for developing improved treatments.     

Vitamin D receptor variants and breast cancer risk in the Polish population

The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the individual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33–2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71–3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.     

Vitamin D and cancer

Vitamin D, a fat-soluble prohormone is synthesized in response to sunlight. Experimental evidence suggests that vitamin D may reduce the risk of cancer through regulation of cellular proliferation and differentiation as well as inhibition of angiogenesis. These anticancer properties have been attributed primarily to 1,25-dihydroxyvitamin D [1,25(OH) 2 D] (calcitriol), the hormonal form of vitamin D. Extensive research has shown that cells, including cancer cells, express specific receptors (VDR) for 1,25-dihydroxyvitamin D. When bound to the VDR, 1,25-dihydroxyvitamin D regulates> 60 genes that exert prodifferentiating, antiproliferative and antimetastatic effects on cells, including effects on cell cycle. The amount of exposure to the sun has been found to correlate inversely with cancer mortality and survival in numerous epidemiological studies. An inverse relationship between solar ultraviolet-B (UV-B) exposure and non-skin cancer mortality has long been reported. Several ecological studies suggest that sunlight may protect against prostate, colon, rectal, female breast and ovarian cancer, all diseases that contribute to a substantially higher proportion of cancer mortality in the western industrialized world. Some analytical studies also suggest a protective association between circulating vitamin D in blood, which is largely derived from sunlight, or dietary vitamin D. Paricalcitol (calcitriol analogue) is as effective as 1,25-dihydroxyvitamin D in transactivating the prostatic VDR and in inhibiting the growth of prostate cancer cell lines and primary cultures of prostate cancer cells in vitro. Promising preclinical evaluations of calcitriol and analogues have appeared in prostate cancer animal models.     

NKG2D signaling in cancer immunosurveillance

The immune system is able to detect and eliminate transformed cells. The activating receptor NKG2D is particularly relevant for cancer immunosurveillance. NKG2D ligand expression renders tumor cells more susceptible to be killed by NK and T cells, and correlates with the clinical outcome of the disease. However, tumors develop mechanisms to overcome the NKG2D‐mediated immune response, which has been associated with poor prognosis and impairment of the clinical benefits of immunotherapy in many human cancers. The highly specific pattern of expression displayed by the NKG2D ligands, mainly confined to tumor cells, together with the strong immune response triggered by this receptor clearly supports the idea that the NKG2D‐mediated pathway may be a powerful target for the treatment of cancer. This review draws together the most recent discoveries concerning the biology of the NKG2D signaling and their therapeutic relevance in the context of cancer.     

Effects of tumor promoters on growth and on cellular redistribution of phospholipid/Ca2+-dependent protein kinase in human breast cancer cells

Active, structurally unrelated tumor promoters (12-0-tetradecanoyl-phorbol-13-acetate (TPA), teleocidin and aplysiatoxin) inhibit growth of mammary carcinoma cells (MCF7- greater than BT-20 greater than MDA-MB-231 greater than = ZR-75-1 greater than HBL-100). This efficiency in inhibiting cell growth correlates with the tumor-promoting activity of a series of phorbol ester derivatives. The phospholipid/calcium-dependent protein kinase (PKC), a target for phorbol ester action, was measured by polyacrylamide gel electrophoresis. The levels of PKC were higher (p less than 0.001) in estrogen-receptor-negative than in estrogen-receptor-positive cells. Treatment of cells with active tumor promoters results in time- and dose-dependent translocation of cytosolic PKC to membrane fractions. Less potent phorbol esters induce only partial translocation of PKC (i.e., decrease of cytosolic without increase in membrane-bound PKC), whereas inactive esters have no effect. No correlation was found between PKC concentration or the amount of PKC translocated to membranes and the sensitivity of the respective cells to TPA. It is concluded that tumor-promoter-mediated growth inhibition of breast cancer cell lines is due to mechanism(s) occurring after the translocation of PKC.     

Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk

Introduction  

Vitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined.     

Vitamin D analogues suppress IGF-I signalling and promote apoptosis in breast cancer cells

Survival factors are known to promote cell viability, and factor deprivation can be a potent apoptotic signal. Insulin-like growth factors are potent mitogens and inhibitors of apoptosis for many normal and neoplastic cells with insulin-like growth factor-I (IGF-I) being the most effective in many breast cancer cell lines. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogues inhibit IGF-I-stimulated growth of MCF-7 human breast cancer cells. The aim of this study was to determine the relationship between inhibition of IGF-I responsiveness and induction of apoptosis by vitamin D analogues in breast cancer cells. Vitamin D analogues EB1089 and CB1093 inhibited autonomous and IGF-I-stimulated growth of MCF-7 and T47D cells and autonomous growth of IGF-I-insensitive Hs578T cells. In MCF-7 cells, IGF-I alone (4 nM) protected against apoptosis mediated by serum deprivation. Co-treatment with vitamin D analogues prevented the anti-apoptotic effects of IGF-I. In T47D cells, IGF-I treatment provided only partial protection against apoptosis induced by serum deprivation and co-incubation of serum-deprived cells with 100 nM CB1093 and IGF-I abrogated this partial protection. In Hs578T cells, addition of IGF-I did not prevent apoptosis induced by serum deprivation. However, treatment with CB1093 attenuated the protective effect of the serum in these cells. Our findings suggest that vitamin D analogues inhibit IGF-I signalling pathways to promote apoptosis in breast cancer cells.     

Vitamin D receptor genotype and breast cancer in Latinas (United States)

Objective: Polymorphism in the vitamin D receptor (VDR) gene has been associated with variation in bone mineral density and with prostate cancer risk. The purpose of this study was to determine whether polymorphism in the VDR gene may also influence breast cancer risk.Methods: Polymorphisms in the 5 and 3 ends of the VDR gene were genotyped for 143 Latina women with breast cancer and 300 cohort controls.Results: Both the BsmI and poly-A polymorphisms in the 3 end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increasing number of BsmI B alleles or short (S) poly-A alleles. Compared to subjects having two long poly-A alleles (genotype LL), odds ratios (and 95% confidence intervals) were 1.5 (1.0–2.3) and 3.2 (1.5–6.9) for subjects having genotypes SL and SS, respectively. Compared to BsmI genotype bb, odds ratios (and 95% confidence intervals) were 1.6 (1.1–2.5) and 2.2 (1.0–4.7) for genotypes Bb and BB respectively. The start codon polymorphism, FokI, was not associated with breast cancer risk.Conclusion: These results suggest that polymorphic variation in or near the 3 end of the VDR gene influences breast cancer risk in Latina women.     

Vitamin D intake and breast cancer risk: a case-control study in Italy

Background: Vitamin D has been suggested to play a protectiverole against several cancers, including breast cancer. Patients and methods: We used data from a case–controlstudy conducted in Italy from 1991 to 1994 to study the relationbetween dietary intake of vitamin D and breast cancer risk.Subjects were 2569 women with incident, histologically confirmedbreast cancer and 2588 hospital controls. Odds ratios (ORs)and 95% confidence intervals (CIs) according to deciles of vitaminD intake were estimated by multiple logistic regression models. Results: After allowance for major risk factors for breast cancerand dietary covariates including calcium and energy intake,there was no association with vitamin D up to the seventh decile.Thereafter, the OR declined, so that the overall trend was statisticallysignificantly inverse. The OR for subjects in the three highestdeciles of consumption compared with those in the lowest onescombined was 0.79 (95% CI 0.70–0.90). Intake of vitaminD >3.57 µg or 143 IU appeared to have a protectiveeffect against breast cancer. The inverse association was consistentacross strata of menopausal status. Conclusions: This study adds to the existing evidence that vitaminD intake in inversely associated with breast cancer risk. Key words: breast cancer, case–control study, risk factors, vitamin D Received for publication October 30, 2007. Revision received May 5, 2008. Accepted for publication July 9, 2008.     

Selective blockade of T-type Ca2+ channels suppresses human breast cancer cell proliferation

We have measured the expression of T-type Ca2+ channel mRNA in breast cancer cell lines (MCF-7 (ERalpha+) using Western blot and quantitative real-time PCR (Q-RT-PCR). These results revealed that the MCF-7 cells express both alpha1G and alpha1H isoforms of T-type Ca2+ channels. In order to further clarify the role of T-type Ca2+ channels in proliferation, we tested the effects of a selective T-type Ca2+ channel inhibitor NNC-55-0396 on cellular proliferation. MCF-7 (ERalpha+) cellular proliferation was inhibited by the compound. In contrast, NNC-55-0396 at same concentration had no effect on the proliferation of MCF-10A cells, a non-cancer breast epithelial cell line. We also found that message expression of the T-type Ca2+ channels were only expressed in rapidly growing non-confluent cells but not in the cytostatic confluent cells. Knocking down the expression of T-type Ca2+ channels with siRNA targeting both alpha1G and alpha1H resulted in growth inhibition as much as 45%+/-5.0 in MCF-7 cells as compared to controls. In conclusion, our results suggest that T-type Ca2+ channel antagonism/silencing may reduce cellular proliferation in mitogenic breast cells.