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Ingles, Sue A.; Garcia, Diana Gonzalez; Wang, Wei; Nieters, Alexandra; Henderson, Brian E.; Kolonel, Laurence N.; Haile, Robert W.; Coetzee, Gerhard A.

doi:10.1023/a:1008979417618

Cited by 114 publications

(34 citation statements)

References 32 publications

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“…These data encouraged several study groups to enlarge the investigations with regard to breast cancer. Two studies revealed a 4-fold higher risk of metastatic spread in breast cancer patients showing the Bsm I restriction site in the VDR gene [12, 13]. The aa genotype indicates a significantly increased risk of developing breast cancer [17].…”

Section: Discussionmentioning

confidence: 99%

“…The allelic variations are indicative of an increased risk of breast cancer. Furthermore, breast cancer patients with a particular VDR genotype have an increased risk of lymph node involvement of the tumor or occult metastases [11, 12, 13]. However, in none of the studies performed so far, the likelihood of developing bone metastases has been associated with a specific VDR genotype.…”

Section: Introductionmentioning

confidence: 99%

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Association of the Vitamin D Receptor Genotype with Bone Metastases in Breast Cancer Patients

Schöndorf¹,

Eisberg²,

Wassmer

et al. 2003

Oncology

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This study was designed in order to evaluate specific vitamin D receptor (VDR) genotypes as indicators of the likelihood of developing osseous metastases in breast cancer patients. Therefore, we determined polymorphisms of the VDR gene in a study group comprising 183 breast cancer patients. Specific fragments spanning over intron 8 and exon 9 of the VDR gene were amplified by polymerase chain reaction. The fragments were then incubated with each of the specific endonucleases ApaI, BsmI or TaqI, respectively. The VDR gene polymorphisms were detected by the presence or absence of the particular restriction site using agarose gel electrophoresis. Statistical analyses revealed a significant correlation between both the VDR gene polymorphisms indicated as AA (absence of the ApaI restriction site in both alleles) or TT (absence of the TaqI restriction site in both alleles), respectively, and the occurrence of bone metastases. Patients with the AA genotype have a 1.7-fold increased risk of developing bone metastases, whereas patients with the TT genotype have a 0.5-fold risk. Neither other genotypes nor allelic combinations displayed any further correlation with the clinical stage. The data suggest that the AA genotype of the VDR gene might be useful to identify breast cancer patients with a high probability of forming occult bone metastases who are considered to benefit from an adjuvant bone-protective therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of the Vitamin D Receptor Genotype with Bone Metastases in Breast Cancer Patients

Schöndorf¹,

Eisberg²,

Wassmer

et al. 2003

Oncology

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“…One example includes BsmI restriction site polymorphisms, which occur in the intron separating exons VIII and IX, and are linked with another polymorphism, a poly(A) microsatellite located in the 3 0 UTR (Ingles et al, 2000). The BB genotype has been associated with higher circulating 1,25(OH) 2 D levels , and with lower risk of breast cancer in some (Yamagata et al, 1997;Ruggiero et al, 1998;Bretherton-Watt et al, 2001) but not all (Ingles et al, 2000;Hou et al, 2002) studies. Findings for colon cancer (Slattery et al, 2001) and prostate cancer (Ingles et al, 1997) also support a potential protective effect of this polymorphism or haplotypes containing this polymorphism.…”

Section: Gene-diet Interactionsmentioning

confidence: 99%

Diet and cancer prevention

2004

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Dietary effects are presumed to underlie many of the large international differences in incidence seen for most cancers. Apart from alcohol and a few micronutrients, however, the role of specific nutritional factors remains illdefined. The evidence for a role of energy balance, physical inactivity, and obesity has strengthened, while for dietary fat it has weakened. Phytochemicals such as folate, lycopene and flavonoids are still the subject of active research. As the mechanisms underlying human carcinogenesis are better understood, dietary research will focus increasingly on intermediate markers such as the insulin-like growth factors and potentially carcinogenic metabolites.

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“…However, prostate cancer cells display a spectrum of sensitivities to the antiproliferative action of 1a,25(OH) 2 D 3 (reviewed in Chen and Holick (2003), Krishnan et al (2003) and Peehl and Feldman (2003)). Reflective of an antiproliferative role, epidemiological studies have now linked the incidence of prostate cancer to low serum levels of 25(OH)D 3 as a result of either diet or environment, and specific VDR polymorphisms have been correlated with cancer susceptibility (Hanchette and Schwartz, 1992;Ingles et al, 1998). Collectively, such data implicate 1a,25(OH) 2 D 3 with a protective action against uncontrolled prostate growth; that initiation or progression of prostate cancer may relate to reduced dietary intake and/or cellular resistance to the antiproliferative effects of 1a,25(OH) 2 D 3 .…”

Section: Introductionmentioning

confidence: 99%

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells

et al. 2004

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We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1a,25-dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (Po0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1a,25(OH) 2 D 3 can be 'restored' by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 nM) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1a,25(OH) 2 D 3 plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1a,25(OH) 2 D 3 plus TSA cooperatively upregulated eight (outof1176)genes,includingMAPK-APK2andGADD45a. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45a induction by 1a,25(OH) 2 D 3 alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45a was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1a,25(OH) 2 D 3 -insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.

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Abstract: These results suggest that polymorphic variation in or near the 3' end of the VDR gene influences breast cancer risk in Latina women.

Cited by 114 publications

References 32 publications

Association of the Vitamin D Receptor Genotype with Bone Metastases in Breast Cancer Patients

Association of the Vitamin D Receptor Genotype with Bone Metastases in Breast Cancer Patients

Diet and cancer prevention

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells

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