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)

While all three coactivators ARA70, steroid receptor coactivator 1, and RAC3/ACTR can enhance androgen receptor (AR) transcriptional activity at 1 nM dihydrotestosterone, we here demonstrate that only ARA70 can induce AR transcriptional activity >30-fold in the presence of 10 nM 17beta-estradiol (E2), but not diethylstilbestrol. The significance of this newly described E2-induced AR transcriptional activity in DU145 human prostate cancer cells was further strengthened by finding patients with Reifenstein partial-androgen-insensitive syndrome that fail in the E2-AR-ARA70 pathway. Together, our data suggest, for the first time, testosterone/dihydrotestosterone may not be the only ligands for the AR. E2 represents another important natural ligand for AR that may play an essential role for the AR function and the development of the male reproductive system.
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PMID:From estrogen to androgen receptor: a new pathway for sex hormones in prostate. 957 16

In an earlier report, we showed that a shorter CAG repeat length in the androgen receptor (AR) gene is associated with an increased risk of prostate cancer in China, the population with the lowest reported prostate cancer incidence in the world. Because AR coactivators enhance transactivation of AR, in this report we evaluated the relationship of a CAG/CAA repeat length polymorphism in the AIB1/SRC-3 gene (amplified in breast cancer gene 1, a steroid receptor coactivator and an AR coactivator) with prostate cancer risk in a population-based case-control study in China. Genomic DNA from 189 prostate cancer patients and 301 healthy controls was used for the PCR-based assay. The AIB1/SRC-3 CAG/CAA repeat length ranged from 24 to 32, with the most common repeat length being 29. Homozygous 29/29 and heterozygous 28/29 were the most common genotypes, with 44 and 30% of the controls harboring these genotypes, respectively. Relative to subjects homozygous for 29 CAG/CAA repeats (29/29 genotype), individuals with the <29/29 genotype had a nonsignificant 31% increased risk [odds ratio (OR), 1.31; 95% confidence interval (CI), 0.87-1.97], whereas those homozygous for the <29 allele had a significant 81% excess risk (OR, 1.81; 95% CI, 1.00-3.28). The combined effect of CAG repeat lengths in the AR and AIB1/SRC-3 genes was also evaluated. Relative to men with both the 29/29 genotype of the AIB1/SRC-3 gene and a long CAG repeat length (> or =23) in the AR gene, those with both the <29/<29 AIB1/SRC-3 genotype and a short CAG repeat length in the AR gene (<23) had a 2.8-fold risk (OR, 2.78; 95% CI, 1.24-6.26). Together, our data indicate that the CAG/CAA repeat length in the AIB1/SRC-3 gene may be associated with prostate cancer risk in Chinese men and that the combination of CAG/CAA repeat lengths in both the AIB1/SRC-3 and AR genes may provide a useful marker for clinically significant prostate cancer. Expanded studies in other populations are needed to confirm this association and the combined effect of AIB1/SRC-3 and other hormone-related genes in prostate cancer etiology.
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PMID:Polymorphic CAG/CAA repeat length in the AIB1/SRC-3 gene and prostate cancer risk: a population-based case-control study. 1192 93

Steroid receptor coactivator 3 (SRC-3/p/CIP/AIB1/ACTR/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 (NCoA-1) and SRC-2 (TIF2/GRIP1/NCoA2). Previous studies indicate that SRC-3 is required for normal animal growth and is often amplified or overexpressed in many cancers, including breast and prostate cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell lines. Furthermore, our results indicate that overexpression of SRC-3 can modulate the AKT signaling pathway in a steroid-independent manner, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA decreases cell growth, leading to a smaller cell size. Similarly, in SRC-3 null mutant mice, AKT signaling is down-regulated in normally SRC-3-expressing tissues. Taken together, these results suggest that SRC-3 is an important modulator for mammalian cell growth.
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PMID:Role of the steroid receptor coactivator SRC-3 in cell growth. 1456 19

Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.
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PMID:Expression and function of androgen receptor coactivators in prostate cancer. 1566 89

Prostate cancer is the most common cancer in men in America. Currently, steroid receptor coactivators have been proposed to mediate the development and progression of prostate cancer, at times in a steroid-independent manner. Steroid receptor coactivator-3 (SRC-3, p/CIP, AIB1, ACTR, RAC3, and TRAM-1) is a member of the p160 family of coactivators for nuclear hormone receptors including the androgen receptor. SRC-3 is frequently amplified or overexpressed in a number of cancers. However, the role of SRC-3 in cancer cell proliferation and survival is still poorly understood. In this study, we show that SRC-3 is overexpressed in prostate cancer patients and its overexpression correlates with prostate cancer proliferation and is inversely correlated with apoptosis. Consistent with patient data, we have observed that reduction of SRC-3 expression by small interfering RNA decreases proliferation, delays the G1-S transition, and increases cell apoptosis of different prostate cancer cell lines. Furthermore, with decreased SRC-3 expression, proliferating cell nuclear antigen and Bcl-2 expression, as well as bromodeoxyuridine incorporation in prostate cancer cells are reduced. Finally, knockdown of SRC-3 with inducible short hairpin RNA expression in prostate cancer cells decreased tumor growth in nude mice. Taken together, these findings indicate that SRC-3 is an important regulator of prostate cancer proliferation and survival.
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PMID:SRC-3 is required for prostate cancer cell proliferation and survival. 1614 Sep 70

Androgen receptor (AR) is a ligand-induced transcriptional factor, which plays an important role in the normal development of prostate as well as in the progression of prostate cancer. Numerous coactivators, which associate with AR and function to remodel chromatin and recruit RNA polymerase II to enhance the transcriptional potential of AR, have been identified. Among these coactivators, few are protein kinases. In this study, we describe the characterization of a novel protein kinase, male germ cell-associated kinase (MAK), which serves as a coactivator of AR. We present evidence, which indicates that (a) MAK physically associates with AR (MAK and AR are found to be coprecipitated from cell extracts, colocalized in nucleus, and corecruited to prostate-specific antigen promoter in LNCaP as well as in transfected cells); (b) MAK is able to enhance AR transactivation potential in an androgen- and kinase-dependent manner in several prostate cancer cells and synergize with ACTR/steroid receptor coactivator-3 coactivator; (c) small hairpin RNA (shRNA) knocks down MAK expression resulting in the reduction of AR transactivation ability; (d) MAK-shRNA or kinase-dead mutant, when introduced into LNCaP cells, reduces the growth of the cells; and (e) microarray analysis of LNCaP cells carrying kinase-dead MAK mutant showed a significant impediment of AR signaling, indicating that endogenous MAK plays a general role in AR function in prostate cancer cells and likely to be a general coactivator of AR in prostate tissues. The highly restricted expression of this kinase makes it a potentially useful target for intervention of androgen independence.
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PMID:Male germ cell-associated kinase, a male-specific kinase regulated by androgen, is a coactivator of androgen receptor in prostate cancer cells. 1695 Nov 54

Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes. SRC-3 is frequently amplified and/or overexpressed in hormone-sensitive and hormone-insensitive tumors. We reported previously that SRC-3 stimulated prostate cell growth in a hormone-independent manner through activation of AKT signaling pathway. However, the underlying mechanism remains undefined. Here, we exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis. We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival. In contrast, knockdown of SRC-3 in PC3 (androgen receptor negative) prostate cancer cells and MCF-7 breast cancer cells reduces their expression. Similarly, in prostate glands of SRC-3 null mice, expressions of these components in the IGF/AKT signal pathway are also reduced. Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3. Interestingly, we showed that recruitment of SRC-3 to two target promoters, IRS-2 and IGF-I, requires transcription factor activator protein-1 (AP-1). Taken together, our results clearly show that SRC-3 and AP-1 can coordinately regulate the transcription of multiple components in the IGF/AKT pathway to ensure ligand-independent cell proliferation and survival of cancer cells.
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PMID:Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway. 1710 43

Although the amplified-in-breast cancer 1 (AIB1; SRC-3, ACTR, or NCoA3) was defined as a coactivator for androgen receptor (AR) by in vitro studies, its role in AR-mediated prostate development and prostate cancer remained unexplored. We report here that AIB1 is expressed in the basal and stromal cells but not in the epithelial cells of the normal mouse prostates. AIB1 deficiency only slightly delayed prostate growth and had no effect on androgen-dependent prostate regeneration, suggesting an unessential role of AIB1 in AR function in the prostate. Surprisingly, when prostate tumorigenesis was induced by the SV40 transgene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, AIB1 expression was observed in certain epithelial cells of the prostate intraepithelial neoplasia (PIN) and well-differentiated carcinoma and in almost all cells of the poorly differentiated carcinoma. After AIB1 was genetically inactivated in AIB1-/-/TRAMP mice, the progression of prostate tumorigenesis in most AIB1-/-/TRAMP mice was arrested at the well-differentiated carcinoma stage. Wild-type (WT)/TRAMP mice developed progressive, multifocal, and metastatic prostate tumors and died between 25 and 34 weeks. In contrast, AIB1-/-/TRAMP mice only exhibited PIN and early-stage well-differentiated carcinoma by 39 weeks. AIB1-/-/TRAMP prostates showed much lower cell proliferation than WT/TRAMP prostates. Most AIB1-/-/TRAMP mice could survive more than 35 weeks and died with other types of tumors or unknown reasons. Our results indicate that induction of AIB1 expression in partially transformed epithelial cells is essential for progression of prostate tumorigenesis into poorly differentiated carcinoma. Inhibition of AIB1 expression or function in the prostate epithelium may be a potential strategy to suppress prostate cancer initiation and progression.
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PMID:Genetic ablation of the amplified-in-breast cancer 1 inhibits spontaneous prostate cancer progression in mice. 1757 67

Steroid receptor coactivator-3 (SRC-3)/AIB1 is a member of the p160 nuclear receptor coactivator family involved in development and cell cycle progression. We previously showed that SRC-3/AIB1 is required for prostate cancer cell proliferation and survival. Here, we reported that the elevated SRC-3/AIB1 expression is significantly correlated with human prostate cancer seminal vesicle invasion and lymph node metastasis. Furthermore, SRC-3/AIB1 is associated with increased prostate cancer cell migration and invasion. SRC-3/AIB1 is required for focal adhesion turnover and focal adhesion kinase activation. In addition, SRC-3/AIB1 directly regulates transcription of matrix metalloproteinase (MMP)-2 and MMP-13 through its coactivation of AP-1 and PEA3. Taken together, these data suggest that SRC-3/AIB1 plays an essential role in prostate cancer cell invasion and metastasis.
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PMID:Steroid receptor coactivator-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression. 1859 49

The androgen and androgen receptor (AR)-regulated gene expression plays important roles in normal prostate and prostate cancer development, and AR transcriptional control of genes is mediated by transcriptional coactivators, including the three members of the steroid receptor coactivator (SRC) family, SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2) and SRC-3 (AIB1, ACTR/RAC3/NCOA3). SRC-1 and SRC-3 are overexpressed in multiple human endocrine cancers and knockdown of either one of them in prostate cancer cell lines impedes cellular proliferation. Knockout of SRC-3 in mice suppresses the progression of spontaneous prostate carcinogenesis. In this study, we investigated SRC-1 contribution to prostate cancer in vivo by deleting the SRC-1 gene in TRAMP mice, which contain the probasin promoter-driven SV40 T/t antigen transgene. In assessing tumor mass of mice at various ages, we found that initiation and progression of prostate cancer induced by SV40 T/t antigens were unaltered in SRC-1(-/-) mice versus WT mice. Primary tumor histology and metastasis to distant lymph nodes were also similar in these mice at all time points assessed. These results demonstrate that the role of SRC-1 in mouse prostate carcinogenesis is nonessential and different from the essential contribution of SRC-3 that is required for prostate cancer progression and metastasis in mice. Interestingly, we observed that during prostate tumorigenesis SRC-1 expression was relatively constant, while SRC-3 expression was significantly elevated. Therefore, the loss of SRC-1 function may be compensated by SRC-3 overexpression during prostate tumorigenesis in SRC-1(-/-) mice.
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PMID:The role of SRC-1 in murine prostate cancinogenesis is nonessential due to a possible compensation of SRC-3/AIB1 overexpression. 1930 43


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