Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Mxi1 protein negatively regulates Myc oncoprotein activity and thus potentially serves a tumour suppressor function. MXI1 maps to chromosome 10q24-q25, a region that is deleted in some cases of prostate cancer. We have detected mutations in the retained MXI1 alleles in four primary prostate tumours with 10q24-q25 deletions. Two tumours contained inactivating mutations, whereas two others contained the identical missense mutation. Fluorescence in situ hybridization also demonstrated loss of one MXI1 allele in an additional tumour lacking chromosome 10 abnormalities. MXI1 thus displays allelic loss and mutation in some cases of prostate cancer that may contribute to the pathogenesis or neoplastic evolution of this common malignancy.
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PMID:Mutation of the MXI1 gene in prostate cancer. 777 87

There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility.
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PMID:No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group. 937 79

For prostate cancer, allelic deletions from the long arm of chromosome 10 (#10q23-25), the locus of the putative tumor suppressor gene MXI1 (#10q24-25), have been identified as a frequently occurring genetic event. During the development of several human malignancies, the c-myc proto-oncogene has been identified to enhance cellular transformation, mitogenesis and cell proliferation. The MXI1 gene, belonging to the helix-loop-helix (bHLH) gene family, was demonstrated to display tumor suppressor function by antagonizing c-myc induced transcriptional activities. Due to the detection of point mutations in the retained alleles of four primary adenocarcinomas of the prostate, MXI1 gene alterations have been suggested to be involved in the development and/or the progression of prostate cancer. To evaluate the role of MXI1 gene alterations for the development of adenocarcinoma of the prostate, 42 primary prostate cancers of different stage (T1-4) and histological grade (G1-3) were investigated for alterations within exons 4 and 5 of the MXI1 gene (spanning 6 exons in total), encoding for the functional HLH-Zip domain, by RNA-SSCP analysis and direct PCR-DNA-sequencing following the microscopically guided tumor cell dissection from 5 microm fresh-frozen buffer-soaked tissue sections. Even by application of this highly elaborated technical approach, MXI1 gene alterations could not be deleted in any of the tumor specimens investigated. Therefore, a substantial involvement of MXI1 gene alterations in the development of prostate cancer appears unlikely. The newly identified putative tumor suppressor gene PTEN, located at #10q23, might be responsible for the frequently observed allelic deletions from #10q23-25 in prostate cancer.
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PMID:The MXI1 tumor suppressor gene is not mutated in primary prostate cancer. 945 79

One of the most common chromosomal abnormalities in prostate cancer involves loss of 10q22-qter. Rarely, a smaller deletion, involving 10q24-q25, has been observed, suggesting the presence of a tumor suppressor gene at this site. We previously demonstrated that the MXI1 gene maps to 10q24-q25 and is mutated in some tumors with cytogenetically detectable deletions of this locus. MXI1 encodes a basic-helix-loop-helix protein that suppresses the transcriptional activity of the MYC oncoprotein by competing for the common dimerization partner, MAX, and binding to identical DNA sites. Because more than 90% of prostate tumors contain no cytogenetic abnormality of 10q, the relevance of MXI1 loss and/or mutation to the vast majority of cases remains unclear. We prospectively evaluated prostate tumors for loss of MXI1 by fluorescence in situ hybridization (FISH) and cytogenetic techniques. Twenty-one of 40 tumors (53%) demonstrated loss of a single MXI1 allele as determined by FISH. Ten cases with cytogenetically normal 10qs, but with FISH-documented deletion of MXI1, were examined at the molecular level, and eight mutations were identified, albeit at low frequency. Five of the mutant proteins were unable to bind DNA in association with MAX. We conclude that MXI1 gene loss in prostate cancer is common and most frequently involves a cytogenetically undetectable deletion.
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PMID:Commonly occurring loss and mutation of the MXI1 gene in prostate cancer. 966 67

We examined 11 prostate cancer xenografts and 4 cell lines for chromosome 10 alterations. Conventional comparative genomic hybridization (CGH) and array-based CGH revealed a pattern of loss of distal 10p, gain of proximal 10p and 10q, and loss of distal 10q. In addition, array CGH identified 2 high-level amplifications in the cell line PC3, homozygous deletions of PTEN in PC3 and in the xenografts PCEW, PC133, and PC324, and small single- or double-copy deletions around PTEN in PCEW, PC82, PC324, PC346, and LNCaP. Allelotype analysis confirmed all 10p losses, 5 of 6 large 10q losses, the homozygous deletions, and the small regions of one copy loss. MXI1, DMBT1, and KLF6 were excluded as important tumor-suppressor genes. The sizes of homozygous deletions around PTEN ranged from 1.2 Mbp (PC133) to <30 kbp (PTEN exon 5 in PC295). The regions of small single- or double-copy loss around PTEN were all less than 4.5 Mbp. The loss of 1 or 2 copies of PTEN was always accompanied by loss of the distal flanking gene FLJ11218 and, in most cases, by loss of the proximal flanking genes MINPP1, PAPSS2, and FLJ14600. Furthermore, differential expression was detected for FLJ11218 and PAPSS2. Complete deletion or inactivating mutation of PAPSS2 was found in at least 3 samples. In addition to 4 homozygous deletions, 1 missense mutation was detected in FLJ11218. In conclusion, our data provide evidence that loss of a small region around PTEN is the major chromosome 10 alteration in prostate cancer xenografts and cell lines. In some of the samples, PTEN inactivation was accompanied by loss of 1 MINPP1 allele, loss of 1 copy, mutation, or low expression of PAPSS2, and most frequently by loss of 1 or 2 copies or low expression of FLJ11218.
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PMID:Loss of a small region around the PTEN locus is a major chromosome 10 alteration in prostate cancer xenografts and cell lines. 1473 19

Prostate cancer incidence is steadily increasing in Western industrialized countries where it has become the most common male malignancy and second most common cause of cancer death among men. Despite efforts to understand the mechanisms of prostate cancer development and progression, the reasons for the disease remain unclear. Although recurrent DNA copy number aberrations in prostate cancer have been well documented in the past 15 years, most of the target genes for these aberrations remain to be identified. The most common DNA copy number aberrations are losses in chromosomes 5q, 6q, 8p, 10q, 13q, 16q, 17p, and 18q, and gains in 7p/q, 8q, 9p, and Xq. In addition, a chromosomal rearrangement in 21q has been observed in over 50% of prostate cancers. The target genes for two common chromosomal aberrations have been identified: the androgen receptor (AR) gene at Xq12, and TMPRSS2 and ERG at 21q. Putative target genes for other copy number aberrations include: NKX3-1 (8p loss), PTEN and MXI1 (10q loss), FOXO1A (13q loss), CDH1 and ATBF1 (16q loss), MCM7 and EZH2 (7q gain), TCEB1, EIF3S3 and MYC (8q gain). The identification of target genes for the chromosomal aberrations will provide new prognostic markers and therapeutic targets for future drug development.
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PMID:Chromosomal aberrations in prostate cancer. 1748 99

Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription. Sixteen genes have been associated with cancer, with five specifically associated with prostate cancer (BTG2, IGFBP3, SIRT1, MXI1, and FDPS). Validation was performed on an independent publicly available dataset of 140 patients, where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence. Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors, including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways. Overall, this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer.
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PMID:Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence. 2471 34

Anti-androgen therapies, including orchiectomy, are effective at promoting prostate cancer remission, but are followed by progression to the more aggressive castration-resistant prostate cancer (CRPC). Castration promotes gland and tumor shrinkage. However, prostate adaptation to androgen deprivation involves striking parallel events, all requiring changes in gene expression. We hypothesized that transcription factors (TF) and other transcription-related genes are needed to orchestrate those changes. In this work, downstream analysis using bioinformatic tools and published microarray data allowed us to identify sixty transcriptional regulators (including 10 TF) and to integrate their function in physiologically relevant networks. Functional associations revealed a connection between Arnt, Bhlhe41 and Dbp circadian rhythm genes with the Ar circuitry and a small gene network centered in Pex14, which might indicate a previously unanticipated metabolic shift. We have also identified human homologs and mapped the corresponding genes to human chromosome regions commonly affected in prostate cancer, with particular attention to the PTEN/HHEX/MXI1 cluster at 10q23-25 (frequently deleted in PCa) and to MAPK1 at 22q11.21 (delete in intermediate risk but not in high risk PCa). Twenty genes were found mutated or with copy number alterations in at least five percent of three cancer cohorts and six of them (PHOX2A, NFYC, EST2, EIF2S1, SSRP1 and PARP1) associated with impacted patient survival. These changes are specific to the adaptation to the hypoandrogen environment and seem important for the progression to CRPC when mutated.
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PMID:Transcriptional regulators and regulatory pathways involved in prostate gland adaptation to a hypoandrogen environment. 3215 9

Dysregulation of miRNAs has a fundamental role in the initiation, development and progression of prostate cancer (PCa). The potential of miRNA in gene therapy and diagnostic applications is well documented. To further improve miRNAs' ability to distinguish between PCa and benign prostatic hyperplasia (BPH) patients, nine miRNA (-21, -27b, -93, -141, -205, -221, -182, -375 and let-7a) with the highest reported differentiation power were chosen and for the first time used in comparative studies of serum and prostate tissue samples. Spearman correlations and response operating characteristic (ROC) analyses were applied to assess the capability of the miRNAs present in serum to discriminate between PCa and BPH patients. The present study clearly demonstrates that miR-93 and miR-375 could be taken into consideration as single blood-based non-invasive molecules to distinguish PCa from BPH patients. We indicate that these two miRNAs have six common, PCa-related, target genes (CCND2, MAP3K2, MXI1, PAFAH1B1, YOD1, ZFYVE26) that share the molecular function of protein binding (GO:0005515 term). A high diagnostic value of the new serum derived miR-182 (AUC = 0.881, 95% confidence interval, CI = 0.816-0.946, p < 0.0001, sensitivity and specificity were 85% and 79%, respectively) is also described.
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PMID:MiR-93/miR-375: Diagnostic Potential, Aggressiveness Correlation and Common Target Genes in Prostate Cancer. 3278 53