Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention.
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ABSTRACT:
SUBMITTER: Vietri MT
PROVIDER: S-EPMC8038462 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Circadian genes have been considered as a possible biological mechanism for the observed relationship between circadian rhythm disruptions and increased risk of hormone-related cancers. In the current study, we investigated the relationship between circadian gene variants and prostate cancer risk and whether reducing bioavailable testosterone modifies the circadian genes-prostate cancer relationship. We conducted a nested case-control study among Caucasian men in the Prostate Cancer Prevention Trial (PCPT), a randomized placebo-controlled clinical trial to assess if finasteride (an androgen bioactivation inhibitor) could prevent prostate cancer. We evaluated the associations between 240 circadian gene variations and prostate cancer risk among 1092 biopsy-confirmed prostate cancer cases and 1089 biopsy-negative controls in the study (642 cases and 667 controls from the placebo group; 450 cases and 422 controls from the finasteride group), stratified by treatment group. Among men in the finasteride group, there were suggestive associations between NPAS2 variants and total prostate cancer risk, with one SNP remaining statistically significant after Bonferroni correction (rs746924, odds ratio [OR]?=?1.5, P?=?9.6?×?10-5 ). However, we found little evidence of increased prostate cancer risk (overall or by low/high grade) associated with circadian gene variations in men of the placebo group, suggesting potential modification of genetic effects by treatment. We did not find strong evidence that circadian gene variants influenced prostate cancer risk in men who were not on finasteride treatment. There were suggestive associations between NPAS2 variants and prostate cancer risk among men using finasteride, which warrants further investigations.
| S-EPMC5940353 | biostudies-literature
Project description:Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.
| S-EPMC6075364 | biostudies-literature
Project description:Growing evidence of the microbiome's role in human health and disease has emerged since the creation of the Human Microbiome Project. Recent studies suggest that alterations in microbiota composition (dysbiosis) may play an essential role in the occurrence, development, and prognosis of prostate cancer (PCa), which remains the second most frequent male malignancy worldwide. Current advances in biological technologies, such as high-throughput sequencing, transcriptomics, and metabolomics, have enabled research on the gut, urinary, and intra-prostate microbiome signature and the correlation with local and systemic inflammation, host immunity response, and PCa progression. Several microbial species and their metabolites facilitate PCa insurgence through genotoxin-mediated mutagenesis or by driving tumor-promoting inflammation and dysfunctional immunosurveillance. However, the impact of the microbiome on PCa development, progression, and response to treatment is complex and needs to be fully understood. This review addresses the current knowledge on the host-microbe interaction and the risk of PCa, providing novel insights into the intraprostatic, gut, and urinary microbiome mechanisms leading to PCa carcinogenesis and treatment response. In this paper, we provide a detailed overview of diet changes, gut microbiome, and emerging therapeutic approaches related to the microbiome and PCa. Further investigation on the prostate-related microbiome and large-scale clinical trials testing the efficacy of microbiota modulation approaches may improve patient outcomes while fulfilling the literature gap of microbial-immune-cancer-cell mechanistic interactions.
| S-EPMC9860633 | biostudies-literature
Project description:Background and objectivesTranscriptomic landscape of prostate cancer (PCa) shows multidimensional variability, potentially arising from the cell-of-origin, reflected in serum markers, and most importantly related to drug sensitivities. For example, Aggressive Variant Prostate Cancer (AVPC) presents low PSA per tumor burden, and characterized by de novo resistance to androgen receptor signaling inhibitors (ARIs). Understanding PCa transcriptomic complexity can provide biological insight and therapeutic guidance. However, unsupervised clustering analysis is hindered by potential confounding factors such as stromal contamination and stress-related material degradation.Materials and methodsTo focus on prostate epithelial cell-relevant heterogeneity, we defined 1,629 genes expressed by prostate epithelial cells by analyzing publicly available bulk and single- cell RNA sequencing data. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. Serum markers PSA and PAP was analyzed to predict response to docetaxel chemotherapy in metastatic setting.ResultsWe identified two luminal subtypes and two aggressive variant subtypes of PCa: luminal A (Adipogenic/AR-active/PSA-high) (30.0%); luminal S (Secretory/PAP-high) (26.0%); AVPC-I (Immune-infiltrative) (14.7%), AVPC-M (Myc-active) (4.2%), and mixed (25.0%). AVPC-I and AVPC-M subtypes predicted to be resistant to ARI and have low PSA per tumor burden. Luminal A and AVPC-M predicted to be resistant to docetaxel and have high PSA/PAP Ratio. Metastatic PCa patients with high PSA/PAP ratio (>20) had significantly shorter progression-free survival than those with low ratio (≤20) following docetaxel chemotherapy.ConclusionWe propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents.
| S-EPMC8616761 | biostudies-literature
Project description:To identify target genes of oncogenic or tumor suppressive microRNAs in human cancer, several cell lines (bladder cancer, prostate cancer, renal cell carcinoma. lung squamous cell carcinoma and head and neck squamous cell carcinoma) were subject to Agilent whole genome microarray. miR-183 and miR-96 function as oncogene. miR-1, miR-133a, miR-135a, miR-145 and miR-375 function as tumor suppressor The miRNA transfected human cancer cell lines (KK47, T24, A498, PC3, DU145, FaDu, SAS, PC10 and H157) were compared to control cell lines.
| S-ECPF-GEOD-26032 | biostudies-other
Project description:Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.
| S-EPMC4031137 | biostudies-literature
Project description:The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging ("transcriptional convergence") on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs.
| S-EPMC3556896 | biostudies-literature
Project description:The androgen receptor (AR) plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa). However, little is known about AR target genes that mediate the receptor's roles in disease progression.Using Chromatin Immunoprecipitation (ChIP) Display, we discovered 19 novel loci occupied by the AR in castrate resistant C4-2B PCa cells. Only four of the 19 AR-occupied regions were within 10-kb 5'-flanking regulatory sequences. Three were located up to 4-kb 3' of the nearest gene, eight were intragenic and four were in gene deserts. Whereas the AR occupied the same loci in C4-2B (castrate resistant) and LNCaP (androgen-dependent) PCa cells, differences between the two cell lines were observed in the response of nearby genes to androgens. Among the genes strongly stimulated by DHT in C4-2B cells--D-dopachrome tautomerase (DDT), Protein kinase C delta (PRKCD), Glutathione S- transferase theta 2 (GSTT2), Transient receptor potential cation channel subfamily V member 3 (TRPV3), and Pyrroline-5-carboxylate reductase 1 (PYCR1)--most were less strongly or hardly stimulated in LNCaP cells. Another AR target gene, ornithine aminotransferase (OAT), was AR-stimulated in a ligand-independent manner, since it was repressed by AR siRNA knockdown, but not stimulated by DHT. We also present evidence for in vivo AR-mediated regulation of several genes identified by ChIP Display. For example, PRKCD and PYCR1, which may contribute to PCa cell growth and survival, are expressed in PCa biopsies from primary tumors before and after ablation and in metastatic lesions in a manner consistent with AR-mediated stimulation.AR genomic occupancy is similar between LNCaP and C4-2B cells and is not biased towards 5' gene flanking sequences. The AR transcriptionally regulates less than half the genes nearby AR-occupied regions, usually but not always, in a ligand-dependent manner. Most are stimulated and a few are repressed. In general, response is stronger in C4-2B compared to LNCaP cells. Some of the genes near AR-occupied regions appear to be regulated by the AR in vivo as evidenced by their expression levels in prostate cancer tumors of various stages. Several AR target genes discovered in the present study, for example PRKCD and PYCR1, may open avenues in PCa research and aid the development of new approaches for disease management.
| S-EPMC1904239 | biostudies-literature
Project description:The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16-2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)(n) repeat polymorphism in UGT1A1, the heterozygous short (<7 repeats)/long (?7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05-1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment.
| S-EPMC3179424 | biostudies-literature
Project description:Progression of prostate cancer (CaP) relies on androgen receptor (AR) signaling, but AR-dependent events that underlie the lethal phenotype remain unknown. Recently, an indirect mechanism of androgen action in which effects of AR on CaP cells are mediated by Serum Response Factor (SRF) has been identified. This is the first mode of androgen action to be associated with aggressive CaP and disease recurrence. The manner in which androgen-responsive SRF activity controls aggressive CaP cell behavior is unknown. Here, the contribution of two representative SRF effector genes that are underexpressed, calponin 2 (CNN2), or overexpressed, sidekick-homolog 1 (SDK1), in clinical CaP specimens is studied. AR- and SRF- dependency of CNN2 and SDK1 expression was verified using synthetic and natural androgens, antiandrogens, and small interfering RNAs targeting AR or SRF, and evaluating the kinetics of androgen induction and SRF binding to endogenously and exogenously expressed regulatory gene regions in AR-positive CaP model systems that mimic the transition from androgen-stimulated to castration-recurrent disease. Small interfering RNA-mediated deregulation of CNN2 or SDK1 expression did not affect CaP cell proliferation or apoptosis but had marked effects on CaP cell morphology and actin cytoskeleton organization. Loss of CNN2 induced cellular protrusions and increased CaP cell migration, whereas silencing of SDK1 led to cell rounding and blunted CaP cell migration. Changes in cell migration did not involve epithelial-mesenchymal transition but correlated with altered ?1-integrin expression. Taken together, individual androgen-responsive SRF target genes affect CaP cell behavior by modulating cell migration, which may have implications for therapeutic intervention downstream of AR and SRF.
| S-EPMC3731805 | biostudies-other