UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have suggested that vitamin D is an important determinant of prostate cancer risk and inherited polymorphisms in the 3'-untranslated region (3'UTR) of the vitamin D receptor (VDR) gene are associated with the risk and progression of prostate cancer. This study was conducted to explore the association of VDR gene polymorphisms with prostate cancer risk in Japanese men who are considered to be much less influenced by environmental risk factors for prostate cancer. We studied 222 prostate cancer patients, 209 benign prostatic hyperplasia (BPH) patients, 128 male controls who were over 60 years old and without any evidence of prostate cancer or BPH, and 198 female controls. A PCR-RFLP method was used to determine three VDR gene polymorphisms in the 3'UTR characterized by restriction enzymes BsmI, ApaI and TaqI. In the BsmI polymorphism, heterozygosity or homozygosity for the absence of the BsmI restriction site was associated with one-third the risk of prostate cancer (P < 0.0001; odds ratio, 3.31; 95% confidence interval, 2.05-5.32) and with one-half the risk of BPH (P < 0.005; odds ratio, 2.07; 95% confidence interval, 1.33-3.22) compared with the male controls. The TaqI and ApaI polymorphisms did not show any significant association with either prostate cancer or BPH. The results indicate that the BsmI polymorphism in the VDR gene plays a significant role in protection against prostate cancer and BPH. Because of the racial difference in the strength of the linkage disequilibrium between the three polymorphisms, additional studies are required to apply the present results to other racial-ethnic groups.
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PMID:Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. 1066 81

Prostate cancer cells contain specific receptors [vitamin D receptors (VDRs)] for 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1alpha,25(OH)2D3 for prostate cancer therapy. However, because 1alpha,25(OH)2D3 can cause hypercalcemia, analogues of 1alpha,25(OH)2D3 that are less calcemic but that exhibit potent antiproliferative activity would be attractive as therapeutic agents. We investigated the effects of two different types of less calcemic vitamin D compounds, 25-hydroxyvitamin D3 [25(OH)D3] and 19-nor-1alpha,25-dihydroxyvitamin D2 [19-nor-1,25(OH)2D2], and compared their activity to 1alpha,25(OH)2D3 on (a) the proliferation of primary cultures and cell lines of human prostate cancer cells; and (b) the transactivation of the VDRs in the androgen-insensitive PC-3 cancer cell line stably transfected with VDR (PC-3/ VDR). 19-nor-1alpha,25(OH)2D2, an analogue of 1alpha,25(OH)2D3 that was originally developed for the treatment of parathyroid disease, has been shown to be less calcemic than 1alpha,25(OH)2D3 in clinical trials. Additionally, we recently showed that human prostate cells in primary culture possess 25(OH)D3-1alpha-hydroxylase, an enzyme that hydroxylates the inactive prohormone, 25(OH)D3, to the active hormone, 1alpha,25(OH)2D3, intracellularly. We reasoned that the hormone that is formed intracellularly would inhibit prostate cell proliferation in an autocrine fashion. We found that 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar dose-dependent inhibition in the cell lines and primary cultures in the [3H]thymidine incorporation assay and that both compounds were significantly more active in the primary cultures than in LNCaP cells. Likewise, 25(OH)D3 had inhibitory effects comparable to those of 1alpha,25(OH)2D3 in the primary cultures. In the chloramphenicol acetyltransferase (CAT) reporter gene transactivation assay in PC-3/ VDR cells, 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar increases in CAT activity between 10(-11)and 10(-9) M. Incubation of PC-3/VDR cells with 5 x 10(-8) M 25(OH)D3 induced a 29-fold increase in CAT activity, similar to that induced by 10(-8) M 1alpha,25(OH)2D3. In conclusion, our data indicate that 25(OH)D3 and 19-nor-1alpha,25(OH)2D2 represent two different solutions to the problem of hypercalcemia associated with vitamin D-based therapies: 25(OH)D3 requires the presence of 1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2 does not. Both drugs are approved for human use and may be good candidates for human clinical trials in prostate cancer.
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PMID:The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. 1074 14

The vitamin D receptor (VDR) is a member of the steroid/retinoid receptor superfamily of nuclear receptors that has potential tumor-suppressive functions. We show here that VDR interacts with and is regulated by BAG1L, a nuclear protein that binds heat shock 70-kDa (Hsp70) family molecular chaperones. Endogenous BAG1L can be co-immunoprecipitated with VDR from prostate cancer cells (ALVA31; LNCaP) in a ligand-dependent manner. BAG1L, but not shorter non-nuclear isoforms of this protein (BAG1; BAG1M/Rap46), markedly enhanced, in a ligand-dependent manner, the ability of VDR to trans-activate reporter gene plasmids containing a vitamin D response element in transient transfection assays. Mutant BAG1L lacking the C-terminal Hsc70-binding domain suppressed (in a concentration-dependent fashion) VDR-mediated trans-activation of vitamin D response element-containing reporter gene plasmids, without altering levels of VDR or endogenous BAG1L protein, suggesting that it operates as a trans-dominant inhibitor of BAG1L. Gene transfer-mediated elevations in BAG1L protein levels in a prostate cancer cell line (PC3), which is moderately responsive to VDR ligands, increased the ability of natural (1alpha,25(OH)(2) vitamin D(3)) and synthetic (1alpha, 25-dihydroxy-19-nor-22(E)-vitamin D(3)) VDR ligands to induce expression of the VDR target gene, p21(Waf1), and suppress DNA synthesis. Thus, BAG1L is a direct regulator of VDR, which enhances its trans-activation function and improves tumor cell responses to growth-suppressive VDR ligands.
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PMID:BAG1L enhances trans-activation function of the vitamin D receptor. 1096 5

Polymorphisms in the vitamin D receptor (VDR) gene have been analyzed in several studies for an association with prostate cancer (PCA) and odds ratios (OR) > or = 3 have been observed in study populations from North America. We studied three polymorphisms in the VDR gene (poly-A microsatellite, TaqI and FokI RFLPs) in 105 controls and 132 sporadic PCA cases from France and in a collection of families from Germany and France. The polymorphisms near the 3' end of the gene were in linkage disequilibrium with an almost complete coincidence of the short poly-A alleles and t (presence of the restriction site) of the TaqI polymorphism, (contingency tables, P<0.0001). An association was found by logistic regression for the poly-A between PCA and the heterozygous genotype (S/L; S < 17, L > or = 17, OR=0.44, 95% confidence interval, CI=0.198-0.966, P=0.041). OR was lower in patients < or = 70 years old and patients with a Gleason score > or = 6. The Tt genotype of the TaqI RFLP also showed an association with PCA (OR=0.5, CI=0.27-0.92, P=0.026). This association was also stronger for patients < or = 70 years old (OR=0.31, CI=0.15-0.63, P=0.001). The risk alleles were S and t alleles as indicated by the OR of the homozygotes, although these were not significant. The FokI RFLP at the 5' end of the gene did not reveal any association (P>0.7). While some association studies differ between Europe and North America, our present findings with the VDR gene agree with those from North America, indicating a weak but general role of the VDR in PCA susceptibility.
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PMID:Vitamin D receptor polymorphisms as markers in prostate cancer. 1098 58

The anti-proliferative action of the seco-steroid hormone 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] extends to some, but not all breast and prostate cancer cell lines. By elucidating the molecular mechanisms mediating the sensitivity of these cells, we can identify critical target genes regulated directly or indirectly by 1alpha,25(OH)2D3 and pathways potentially disrupted during transformation. In this study, we demonstrated the induction of expression of BRCA1 mRNA and protein as well as transcriptional activation from the BRCA1-promoter by 1alpha,25(OH)2D3 in the sensitive breast cancer cell line MCF-7. This was not observed in the 1alpha,25(OH)2D3-resistant breast cancer cell line MDA-MB-436. The induction of BRCA1 mRNA was blocked by cyclohexamide. This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor (VDR). Inhibition of VDR protein levels by stable transformation of the anti-sense VDR in MCF-7 reduced the sensitivity of MCF-7 to 1alpha,25(OH)2D3 by 50-fold. In addition, the induction of BRCA1 protein and transcriptional activation of a BRCA1 promoter-luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of VDR levels. Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti-proliferative effects of 1alpha, 25(OH)2D3 was strongly associated with an ability to modulate BRCA1 protein. Furthermore, the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to 1alpha,25(OH)2D3 and their ability to modulate BRCA1 expression. Taken together, our data support a model whereby the anti-proliferative effects of 1alpha,25(OH)2D3 are mediated, in part, by the induction of BRCA1 gene expression via transcriptional activation by factors induced by the VDR and that this pathway is disrupted during the development of prostate and breast cancers.
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PMID:The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. 1104 97

The incidence of prostate cancer is related to aging. Its increase in the last 10 years, varies from country to country and according to ethnic group, with its greatest incidence among African-American males and the least among Asian males. Only two risk factors have thus far been clearly established for prostate cancer: familial aggregation and ethnic origin. No dietary or environmental cause has yet been identified for prostate cancer. However, some variations in endogenous factors, such as sex steroids or IGF1 circulating levels, may partly explain differences in risk observed between different populations. Genetic polymorphisms of genes encoding for 5alpha-reductase, androgen receptor, or vitamin D receptor have been associated with different degrees of risk for prostate cancer and may explain variations in risk among ethnic groups or within geographic areas. Different studies support the theory that familial prostate cancer may be hereditary and not due to a similar lifestyle. Thus, familial inheritance is a parameter that must be considered when advising screening in high-risk families. Indeed, the relative risk for first-degree relatives of prostate cancer patients can reach 2, 5 and 11 when, respectively, 1, 2 and 3 first-degree relatives are affected. Some familial forms appear to be associated with transmission of a rare, putative, autosomal dominant gene (0.003-0.06 allele frequency) with a high penetrance (88% at age 85). Using this transmission model and linkage analysis, three predisposing loci on chromosome 1: HPC-1 (hereditary prostate cancer 1: 1q24-25), PCaP (predisposing for prostate cancer: 1q42-43) and CAPB (predisposing for prostate and brain tumor: 1p36) and one locus on chromosome 20 (HPC20: 20q13) have been described. Moreover, X-linked transmission has been suggested and related to another predisposing gene locus: HPCX (Xq27-28). It is possible that a large proportion of familial prostate cancer is due not to segregation of a few major gene mutations transmitted according to a monogenic inheritance, but rather to familial sharing of alleles at many loci, each contributing to a small increase in cancer risk.
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PMID:Heterogeneity in genetic susceptibility to prostate cancer. 1117 5

Our recent epidemiological study (Ahonen et al., Cancer Causes Control 11(2000) (847-852)) suggests that vitamin D deficiency may increase the risk of initiation and progression of prostate cancer. The nested case-control study was based on a 13-year follow-up of about 19000 middle-aged men free of clinically verified prostate cancer. More than one-half of the serum samples had 25OH-vitamin D (25-VD) levels below 50 nmol/l, suggesting VD deficiency. Prostate cancer risk was highest among the group of younger men (40-51 years) with low serum 25-VD, whereas low serum 25-VD appeared not to increase the risk of prostate cancer in older men (>51 years). This suggests that VD has a protective role against prostate cancer only before the andropause, when serum androgen concentrations are higher. The lowest 25-VD concentrations in the younger men were associated with more aggressive prostate cancer. Furthermore, the high 25-VD levels delayed the appearance of clinically verified prostate cancer by 1.8 years. Since these results suggest that vitamin D has a protective role against prostate cancer, we tried to determine whether full spectrum lighting (FSL) during working hours could increase serum 25-VD concentrations. After 1-month exposure, there was no significant increase in the serum 25-VD level, although there was a bias towards slightly increasing values in the test group as opposed to decreasing values in controls. There was no significant change in the skin urocanic acid production. The possibility to use FSL in cancer prevention is discussed. In order to clarify the mechanism of VD action on cell proliferation and differentiation, we performed studies with the rat and human prostates as well prostate cancer cell lines. It is possible that 25-VD may have a direct role in the host anticancer defence activity, but the metabolism of vitamin D in the prostate may also play an important role in its action. We raised antibodies against human 1alpha-hydroxylase and 24-hydroxylase. Our preliminary results suggest that vitamin D is actively metabolised in the prostate. Vitamin D appears to upregulate androgen receptor expression, whereas androgens seem to upregulate vitamin D receptor (VDR). This may at least partially explain the androgen dependence of VD action. VD alone or administered with androgen causes a suppression of epithelial cell proliferation. VD can activate mitogen-activated kinases, erk-1 and erk-2, within minutes and p38 within hours. Also, auto/paracrine regulation might be involved, since keratinocyte growth factor (mRNA and protein) was clearly induced by VD. Based on these studies, a putative model for VD action on cell proliferation and differentiation is presented.
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PMID:Vitamin D and prostate cancer. 1138 70

Operating through the vitamin D receptor (VDR), vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein (IGFBP) expression, suggesting that the vitamin D and insulin-like growth factor (IGF) regulatory systems may operate together to affect prostate cancer. Among 191 newly diagnosed prostate cancer cases and 304 randomly selected population controls in Shanghai, China, we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk. However, we found that among men with the ff FokI genotype, those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile (odds ratio, 0.14; 95% confidence interval, 0.04-0.56; P(trend) < 0.01), whereas among men with the FF and Ff genotypes, IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype (odds ratio, 0.25; 95% confidence interval, 0.07-0.85; P(trend) = 0.02). No such FokI genotype-specific effects were observed for IGF-I or IGF-II. Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Larger studies are needed to confirm these findings and clarify the underlying mechanisms.
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PMID:Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China. 1138 55

Exposure to ultraviolet radiation may reduce prostate cancer risk, suggesting that polymorphism in genes that mediate host pigmentation will be associated with susceptibility to this cancer. We studied 210 prostate cancer cases and 155 controls to determine whether vitamin D receptor (VDR, Taql and Fokl variants), tyrosinase (TYR, codon 192 variant) and melanocortin-1 receptor (MC1R, Arg151Cys, Arg160Trp, Val92Met, Asp294His and Asp84Glu variants) genotypes are associated with risk. UV exposure was determined using a questionnaire. MC1R Arg(160)/Arg(160) homozygotes were at increased risk (P = 0.027, odds ratio = 1.94) while TYR A2/A2 homozygotes were at reduced risk of prostate cancer (P = 0.033, odds ratio = 0.48). These associations remained significant after correction for UV-exposure. Stratification of cases and controls by quartiles of exposure, showed that the protective effect of TYR A1A2 (P = 0.006, odds ratio 0.075) and A2A2 (P = 0.003, odds ratio 0.055) was particularly strong in subjects who had received the greatest exposure. Our data show for the first time, that allelism in genes linked with skin pigment synthesis is associated with prostate cancer risk possibly because it mediates the protective effects of UV. Importantly, susceptibility is associated with an interaction between host predisposition and exposure.
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PMID:Prostate cancer risk: associations with ultraviolet radiation, tyrosinase and melanocortin-1 receptor genotypes. 1172 Apr 36

The purpose of this study was to investigate the TaqI vitamin D receptor (VDR) polymorphism in both Japanese prostate cancer patients and Japanese noncancer controls in order to determine if an association exists between VDR genotype with clinical and pathological risk of prostate cancer patients. This study involved 115 patients with prostate cancer and 133 male age-matched noncancer controls genotyped for a previously described TaqI restriction fragment length polymorphism (RFLP) at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of TaqI restriction site with individuals being classified as TT, Tt, or tt. The genotype tt was higher among the control group (6.0%) compared to the patients with prostate cancer (1.8%), but not so (OR=0.28; 95%o CI, 0.06-1.33; p=0.081). In addition, the genotype TT was statistically higher among patients with locally advanced or metastatic disease (T3/T4/NI/M1) compared to controls (OR=2.52; 95%o CI, 1.21-5.27; p=0.009). Lastly, the genotype TT was statistically higher among patients with poorly differentiated adenocarcinoma compared to controls (OR=5.38; 95%o CI, 1.57-18.50; p=0.002). These data demonstrate that VDR genotype plays an important role in determining the risk of more clinically advanced and pathologically aggressive prostate cancer which is associated with a higher mortality rate in Japanese men.
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PMID:Clinical and pathological significance of vitamin D receptor gene polymorphism for prostate cancer which is associated with a higher mortality in Japanese. 1178 58

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