Expression of androgen receptor and growth factors in premalignant lesions of the prostate

Harper, M. E.; Glynne-Jones, E; Goddard, Lindy; Mathews, Phillip; Nicholson, Robert Ian

doi:10.1002/(sici)1096-9896(1998100)186:2<169::aid-path164>3.0.co;2-w

Cited by 54 publications

(31 citation statements)

References 26 publications

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“…AR expression is not increased in human high-grade PIN or primary PCa (25,(65)(66)(67). This finding is consistent with the interpretation that the increased AR expression in the Pb-mAR mice is not by itself a transforming event, and that PIN in these mice is the result of additional steps.…”

Section: Discussionsupporting

confidence: 86%

Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

Stanbrough

Leav

Kwan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

155

105

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Prostate cancer (PCa) is an androgen dependent disease that can be treated by androgen ablation therapy, and clinical trials are under way to prevent PCa through the reduction of androgen receptor (AR) activity. However, there are no animal models of AR-mediated prostatic neoplasia, and it remains unclear whether the AR is a positive or negative regulator of cell growth in normal prostate secretory epithelium. To assess the direct effects of the AR in prostate epithelium, a murine AR transgene regulated by the rat probasin promoter (Pb) was used to generate transgenic mice expressing increased levels of AR protein in prostate secretory epithelium. The prostates in younger (<1 year) Pb-mAR transgenic mice were histologically normal, but Ki-67 immunostaining revealed marked increases in epithelial proliferation in ventral prostate and dorsolateral prostate. Older (>1 year) transgenic mice developed focal areas of intraepithelial neoplasia strongly resembling human high-grade prostatic intraepithelial neoplasia (PIN), a precursor to PCa. These results demonstrate that the AR is a positive regulator of cell growth in normal prostate epithelium and provide a model system of AR-stimulated PIN that can be used for assessing preventative hormonal therapies and for identifying secondary transforming events relevant to human PCa.

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Section: Discussionsupporting

confidence: 86%

Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

Stanbrough

Leav

Kwan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

155

105

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“…106 There is progressive loss of some markers of secretory differentiation, including prostate-specific antigen, prostatic acid phosphatase, secretory proteins, 94 cytoskeletal proteins, 94 glycoproteins such as blood group antigens, neuroendocrine cells, p-cadherin, 107 fibroblast growth factor-2, 108 inhibin, 109 prostate-specific transglutaminase, 110 androgen receptor expression, 111 insulin-like growth factor binding protein-3, 112 and telomerase. 113 A member of the CIP/KIP family of cyclin-dependent kinase inhibitory proteins, p27KIP1, also showed significant reduction in expression in PIN, cancer, and metastatic cancer when compared with benign prostatic epithelium.…”

Section: Genetic and Molecular Changesmentioning

confidence: 99%

“…113 A member of the CIP/KIP family of cyclin-dependent kinase inhibitory proteins, p27KIP1, also showed significant reduction in expression in PIN, cancer, and metastatic cancer when compared with benign prostatic epithelium. 114 Other markers show progressive increase, including including human glandular kallikrein 2 (hK2), 115 c-erbB-2 (Her-2/neu) and c-erbB-3 oncoproteins, 108,116 c-met proto-oncogene, 41 bcl-2 oncoprotein, 117,118 mutator (RER( þ )) phenotype, 104 epidermal growth factor and epidermal growth factor receptor, 108,119 type IV Collagenase, Lewis Y antigen, TGF-alpha, apoptotic bodies, 71,73,104 mitotic figures, 71 PCNA expression, Ki-67 expression, MIB-1 expression, 111 tenascin-C, 120 aneuploidy and genetic abnormalities, 62,111,121-127 microvessel density, Ep-Cam transmembrane glycoprotein, 128 Insulin-like growth factor binding protein IGFBP-rP1, and p53 mutations, 129 although one group found no p53 expression immunohistochemically in PIN. 130 Prostate-specific membrane antigen, an abundant transmembrane glycoprotein, shows increased expression in PIN and cancer when compared with benign epithelium, 131,132 and this expression was unaffected by short-term androgen deprivation therapy.…”

Section: Genetic and Molecular Changesmentioning

confidence: 99%

High-grade prostatic intraepithelial neoplasia

2004

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High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely preinvasive stage of adenocarcinoma, almost two decades after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen (PSA) concentration or its derivatives and cannot be detected by current imaging techniques, including ultrasound. Most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype, which are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

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“…Molecular markers of early events in the progression of prostate cancer are expected to be altered in PIN. Examples of such early markers are the loss of expression of the cyclindependent kinase inhibitor p27 (FernaÂ ndez et al, 1999), or the overexpression of the EGF receptor (Harper et al, 1998) in PIN.…”

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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Expression of androgen receptor and growth factors in premalignant lesions of the prostate

Cited by 54 publications

References 26 publications

Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

High-grade prostatic intraepithelial neoplasia

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

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