Update of the androgen receptor gene mutations database

Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5a-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5a-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5a-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5a-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5a-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5a-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5a-reductase inhibitors.

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“…Brothman et al, 1990;Gottlieb et al, 1999). Previous investigations, however, have never focused specifically on androgenmetabolic genes.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the androgen receptor (AR) gene is also mutated in some prostate cancer tissues (e.g. Visakorpi et al, 1995;Gottlieb et al, 1999). Thus, the SRD5A2 gene as well as other androgen-metabolic loci together with the AR may play an important role in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

2004

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Section: Introductionmentioning

confidence: 99%

“…Several genetic and molecular alterations are candidates for being responsible for the phenotypic conversion of normal or hyperplastic prostate cells into malignant, invasive cells (reviewed in LoÂ pez and Diamandis, 1998;Gottlieb et al, 1999;Jenster, 1999). Structural and functional alterations a ecting the androgen receptor or its signaling pathways are probably responsible for many of the biological and biochemical changes associated with the neoplastic transformation of prostate epithelial cells (Gottlieb et al, 1999;Jenster, 1999). Other genetic changes, such as mutations in oncogenes (Shen et al, 1995;Sun et al, 1997) and tumor suppressor genes (Brooks et al, 1996;Meyers et al, 1998;Whang et al, 1998) have been implicated in the multistep sequence of prostate carcinogenesis (Whang et al, 1998), and alterations in genes such as HPC1 (Smith et al, 1996) and BRCA1 (Fan et al, 1998) have been evaluated for their implication in familial forms of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology blocks

et al. 2001

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In a search for molecular markers of progression in prostate cancer by means of di erential display, we have identi®ed a new gene, which we have designated PTOV1. Semiquantitative RT ± PCR has established that nine out of 11 tumors overexpress PTOV1 at levels signi®cantly higher than benign prostatic hyperplasia or normal prostate tissue. The human PTOV1 protein consists almost entirely of two repeated blocks of homology of 151 and 147 amino acids, joined by a short linker peptide, and is encoded by a 12-exon gene localized in chromosome 19q13.3. A Drosophila melanogaster PTOV1 homolog also contains two tandemly arranged PTOV blocks. A second gene, PTOV2, was identi®ed in humans and Drosophila, coding for proteins with a single PTOV homology block and unrelated amino-and carboxyl-terminal extensions. A 1.8-Kb PTOV1 transcript was detected abundantly in normal human brain, heart, skeletal muscle, kidney and liver, and at low levels in normal prostate. Immunocytochemical analysis and expression of chimeric GFP-PTOV1 proteins in cultured cells showed a predominantly perinuclear localization of PTOV1. In normal prostate tissue and in prostate adenomas, PTOV1 was undetectable or expressed at low levels, whereas nine out of 11 prostate adenocarcinomas showed a strong immunoreactivity, with a focal distribution in areas of carcinoma and prostatic intraepithelial neoplasia. Therefore, PTOV1 is a previously unknown gene, overexpressed in early and late stages of prostate cancer. The PTOV homology block represents a new class of conserved sequence blocks present in human, rodent and¯y proteins. Oncogene (2001) 20, 1455 ± 1464.

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“…Nevertheless, high levels of androgen-regulated genes products such as prostate specific antigen (PSA) detected in hormoneinsensitive prostate tumors cells support the idea that the signaling pathway involving the androgen receptor (AR) may still be intact but is possibly activated in an androgen-independent manner. 2 To date, four main hypotheses have been developed to understand how the androgen signal transduction pathway could mediate androgen-independent tumor progression: an insaturable overexpression of the wild-type androgen receptor gene, 3 constitutive androgen-receptor gene mutations, 4,5 excessive recruitment of transcriptional coactivators such as ARA, 6 or alterations in the cross-talk between the androgen receptor and the growth factor receptor pathway. 7 Of note is that none of these hypotheses invokes the loss of AR expression, and in each one of them, AR continues to play a pivotal role.…”

Section: Introductionmentioning

confidence: 99%

Specific block of androgen receptor activity by antisense oligonucleotides

Hamy

Brondani

Spoerri

et al. 2003

Prostate Cancer Prostatic Dis

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Claims about molecular mechanisms underlying the resistance to anti-hormones of prostate cancer cells find support in biological experiments, which involve hormone-independent activation of the androgen receptor's (AR) transcriptional activity. In order to test this hypothesis, we attempted to shut down the expression of AR by the means of target-directed antisense oligonucleotides. A set of 49 oligonucleotides matching sequences of the AR mRNA either in the coding sequence or in the 3 0 and 5 0 untranslated regions were synthesized and examined in a cellular AR-dependent reporter system. Five antisense oligonucleotides were identified as highly potent inhibitors of AR-driven gene expression in a cellular reporter assay. These five were further profiled using point-mutated control sequences for the assessment of AR inhibition. In addition the expression of another AR-driven gene, the modulator of PSA expression (gene for inhibition of prostate specific antigen, an endogenous, AR-driven gene) was examined. Finally, we observed that the hormone-independent but AR-mediated transactivation by IGF-1 could also be specifically shut-down by these antisense oligonucleotides. The selection of highly target-restricted antisense oligonucleotides in the prostate cancer cell line LNCaP provided tools to study a central role of the androgen receptor in growth regulation of prostatic cancer cell lines and could be of utility in cancer situations in vivo.

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Update of the androgen receptor gene mutations database

Cited by 115 publications

References 51 publications

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology blocks

Specific block of androgen receptor activity by antisense oligonucleotides

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