Cytogenetic and expression profiles associated with transformation to androgen-resistant prostate cancer

Pang, See‐Tong; Weng, Wen‐Hui; Flores‐Morales, Amilcar; Johansson, Björn; Pourian, Mohammad R.; Nilsson, Peter; Pousette, Åke; Norstedt, Gunnar

doi:10.1002/pros.20328

Cited by 19 publications

(15 citation statements)

References 41 publications

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“…Third, and again highlighting their biological importance, all the genes in our novel disease signature are located at regions of deletions or chromosomal break points in prostate cancer. [48][49][50] It is therefore possible that genomic rearrangements may be the primary reason for their altered expression in prostate cancer. This idea is in accordance with a recent large-scale genomic study of prostate tumors, which found that copy-number alterations are more robust stratifiers of disease grade than mRNA or miRNA expression profiles.…”

Section: Discussionmentioning

confidence: 99%

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

Thompson

Day

Bianco‐Miotto

et al. 2012

Intl Journal of Cancer

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Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes, ID4, NR2F1 and PTGDS, which were expressed at consistently lower levels in clinical prostate cancer compared to nonmalignant tissues, formed a signature that predicted biochemical relapse (hazard ratio 2.2, p 5 0.038). We believe that our findings support the value of this novel mouse model of prostate cancer to identify candidate therapeutic targets and/or biomarkers of human disease.

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Section: Discussionmentioning

confidence: 99%

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

Thompson

Day

Bianco‐Miotto

et al. 2012

Intl Journal of Cancer

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“…A putative epigenetic gene signature including genes involved in DNA methylation (DNMT3A and MBD4), histone methyltransferases (MLL2, MLL3, and NSD1), and the histone acetyltransferase (SRCAP) was identified. Whereas DNMT3A and MBD4 have previously been found to be altered in prostate cancer (39,57), this is not the case for MLL2, MLL3, SRCAP, and NSD1 (reviewed in ref. 26).…”

Section: Discussionmentioning

confidence: 99%

Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development

Bianco‐Miotto

Chiam

Buchanan

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

139

107

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Background: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis.Methods: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions.Results: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort.Conclusions: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis.Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies. Cancer Epidemiol Biomarkers Prev; 19(10); 2611-22. ©2010 AACR.

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“…To date, no specific role for DNMT3A has been shown for genitourinary tract developmental processes, although a myriad of developmental abnormalities results from deleting Dnmt3a in mouse models and conditional Dnmt3a mutant males show impaired spermatogenesis (46). Studies in prostate cancer have shown increased Dnmt3a expression in tumors developing in the TRAMP model (47), and increased DNMT3A expression has been associated with progression to androgen-independent growth in vitro (47,48). SLC43A1 encodes a protein that functions in the sodium-independent transport of neutral amino acids.…”

Section: Discussionmentioning

confidence: 99%

Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Pritchard

Mecham²,

Dumpit³

et al. 2009

Cancer Research

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Studies centered at the intersection of embryogenesis and carcinogenesis have identified striking parallels involving signaling pathways that modulate both developmental and neoplastic processes. In the prostate, reciprocal interactions between epithelium and stroma are known to influence neoplasia and also exert morphogenic effects via the urogenital sinus mesenchyme. In this study, we sought to determine molecular relationships between aspects of normal prostate development and prostate carcinogenesis. We first characterized the gene expression program associated with key points of murine prostate organogenesis spanning the initial in utero induction of prostate budding through maturity. We identified a highly reproducible temporal program of gene expression that partitioned according to the broad developmental stages of prostate induction, branching morphogenesis, and secretory differentiation. Comparisons of gene expression profiles of murine prostate cancers arising in the context of genetically engineered alterations in the Pten tumor suppressor and Myc oncogene identified significant associations between the profile of branching morphogenesis and both cancer models. Further, the expression of genes comprising the branching morphogenesis program, such as PRDX4, SLC43A1, and DNMT3A, was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal developmental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organogenesis to understand cancer phenotypes.

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Cytogenetic and expression profiles associated with transformation to androgen-resistant prostate cancer

Abstract: Our findings may serve as a basis for molecular dissection of the mechanisms involved in development of androgen resistant prostate cancer.

Cited by 19 publications

References 41 publications

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development

Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

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