Abstract:Purpose: Reliable biomarkers that predict prostate cancer outcomes are urgently needed to improve and personalize treatment approaches. With this goal in mind, we individually and collectively appraised common genetic polymorphisms related to estradiol metabolic pathways to find prostate cancer prognostic markers.Methods: The genetic profiles of 526 men with organ-confined prostate cancer were examined to find common genetic polymorphisms related to estradiol metabolic pathways and these findings were replicat… Show more
“…These conflicting results indicate that the role of SULT2B1b in different cancers is varies with the type of cancer. Recently, several single-nucleotide polymorphisms (SNP) in SULT2B1 gene have been reported to be associated with risk of progression in prostate and esophageal carcinomas [28,29]. Additionally, earlier studies demonstrated that expression of SULT2B1b was significantly increased in breast and liver cancer tissues relative to their corresponding non-tumor counterparts [7,30,31].…”
Background/Aims: Overexpression of cytosolic sulfotransferase 2B1b (SULT2B1b) has been commonly found in colorectal and hepatocellular carcinoma, suggesting that SULT2B1b might act as a potential oncogenic protein. However, its clinical significance and biological role in gastric cancer progression remain largely unknown. Methods: Expressions of SULT2B1b in clinical gastric cancer (GC) samples were examined using qRT-PCR and Western blot. Results: SULT2B1b was markedly overexpressed in human GC samples, and positively correlated with vessel density and associated with poor clinical features. We also demonstrated that overexpression of SULT2B1b resulted in increased tumor angiogenesis and tumor growth in mouse GC models. In addition, ablation of SULT2B1b in human GC cells lines BGC823 and MKN45 decreased the capability of the cells to recruit endothelial cells. Moreover, depletion of SULT2B1b in GC cells reduced VEGF-A expression by downregulating SP1 and AP2. Conclusion: Our results suggested that the SULT2B1b-mediated angiogenic pathway could serve as biomarkers for GC diagnosis and prognosis, and suppressing SULT2B1b-mediated angiogenic signaling might be a promising strategy for developing novel GC treatment.
“…These conflicting results indicate that the role of SULT2B1b in different cancers is varies with the type of cancer. Recently, several single-nucleotide polymorphisms (SNP) in SULT2B1 gene have been reported to be associated with risk of progression in prostate and esophageal carcinomas [28,29]. Additionally, earlier studies demonstrated that expression of SULT2B1b was significantly increased in breast and liver cancer tissues relative to their corresponding non-tumor counterparts [7,30,31].…”
Background/Aims: Overexpression of cytosolic sulfotransferase 2B1b (SULT2B1b) has been commonly found in colorectal and hepatocellular carcinoma, suggesting that SULT2B1b might act as a potential oncogenic protein. However, its clinical significance and biological role in gastric cancer progression remain largely unknown. Methods: Expressions of SULT2B1b in clinical gastric cancer (GC) samples were examined using qRT-PCR and Western blot. Results: SULT2B1b was markedly overexpressed in human GC samples, and positively correlated with vessel density and associated with poor clinical features. We also demonstrated that overexpression of SULT2B1b resulted in increased tumor angiogenesis and tumor growth in mouse GC models. In addition, ablation of SULT2B1b in human GC cells lines BGC823 and MKN45 decreased the capability of the cells to recruit endothelial cells. Moreover, depletion of SULT2B1b in GC cells reduced VEGF-A expression by downregulating SP1 and AP2. Conclusion: Our results suggested that the SULT2B1b-mediated angiogenic pathway could serve as biomarkers for GC diagnosis and prognosis, and suppressing SULT2B1b-mediated angiogenic signaling might be a promising strategy for developing novel GC treatment.
“…Finally, the 1245C variant also appears to be a predictor of sensitivity to the steroidal CYP17 inhibitor abiraterone . Genomic variation in estrogen-related genes has also been reported in PCa patients (Lévesque et al 2014). This includes somatic polymorphisms in CYP1B1, HSD17B2, SULT2B1 and COMT genes.…”
Section: Genomic Alterations Implicating Sex Steroids In Prostate Canmentioning
confidence: 95%
“…This includes somatic polymorphisms in CYP1B1, HSD17B2, SULT2B1 and COMT genes. Further, the cumulative number of alterations appears to correlate with poorer outcome (Lévesque et al 2014). Similarly, SNPs in the CYP19A1 aromatase are associated with concomitant changes in serum estrogen levels and poorer PCa survival, but have no effect on PCa incidence (Travis et al 2009, Kanda et al 2015.…”
Section: Genomic Alterations Implicating Sex Steroids In Prostate Canmentioning
Prostate cancer is uniquely dependent on androgens. Despite years of research on the relationship between androgens and prostate cancer, many questions remain as to the biological effects of androgens and other sex steroids during prostate cancer progression. This article reviews the clinical and basic research on the influence of sex steroids such as androgens, estrogens and progesterone within the prostate tumor microenvironment on the progression of prostate cancer. We review clinical studies to date evaluating serum sex steroids as prognostic biomarkers and discuss their respective biological effects within the prostate tumor microenvironment. We also review the link between genomic alterations and sex steroid levels within prostate tumors. Finally, we highlight the links between sex steroid levels and the function of the immune system within the tumor microenvironment. As the context of treatment of lethal prostate cancer evolves over time, an understanding of this underlying biology remains central to developing optimal treatment approaches.
“…Germline variations in genes involved in the biosynthesis and metabolism of androgens and estrogens have been associated with progression of PCa , Levesque et al 2013, 2014a. The relevance of studying steroidogenic pathways in the context of progression of PCa arises from observations that PCa tumor cells can use multiple biotransforming pathways to de novo synthesize more potent hormones (Montgomery et al 2008, Mitsiades et al 2012.…”
Section: Introductionmentioning
confidence: 99%
“…In support of these results, we have recently reported that singlenucleotide polymorphisms (SNPs) in genes associated with E 2 -related metabolic pathways, either individually or in combination, are predictors of progression of PCa. These variants are located in genes encoding cytochrome P450 1B1, which is involved in the production of 4-hydroxy metabolites of E 2 and E 1 (4-OH), catechol-O-methyltransferase, which forms 2-methoxy catechol estrogens, sulfotransferase 2B1, which catalyzes the formation of less-reactive sulfate metabolites, and 17b-hydroxysteroid dehydrogenase type 2, which is involved in the conversion of E 2 to E 1 (Levesque et al 2014a). However, it remains unclear whether the outcome of PCa is influenced by common germline polymorphisms in the estrogen catabolic pathway mediated by UGT1 gene products.…”
The prognostic significance of common deletions in uridine diphospho-glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at the UGT1 locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants of UGT1 are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across the UGT1 locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan-Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for four UGT1 intronic variants with hazard ratios (HRs) of 1.59-1.88 (P!0.002) for htSNPs in UGT1A10, UGT1A9, and UGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns of UGT1A10 and UGT1A9 (HRZ0.56-058; P%0.01). An unfavorable UGT1 haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CIZ1.13-2.50; PZ0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms of UGT1 are potential predictors of recurrence of PCa after prostatectomy.
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