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)

Prostate cancer (CaP) is the most common cancer in adult men in North America. Since there is no naturally occurring prostate cancer in the mouse, preclinical studies stipulate for the establishment of a genetically manipulated mouse CaP model with features close to the human situation. In view of the limitations of transgenic technique-derived CaP models, herein we report the first application of knockin technology to establish a new mouse adenocarcinoma prostate model (PSP-KIMAP) by targeting of SV40 Tag to a prostate tissue-specific gene, PSP94 (prostate secretory protein of 94 amino acids). In order to demonstrate its novelty, we compared KIMAP to a PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP) model. The CaP development of the PSP-KIMAP mice started almost immediately after puberty at 10 weeks of age from mouse prostatic intraepithelial neoplasia (mPIN) with microinvasion to well-differentiated CaP, and demonstrated a close-to-human kinetics of prolonged tumor growth and a predominance of well and moderately differentiated tumors. The invasive nature of KIMAP model was demonstrated by multitissue metastases (lymph node, lung and liver etc) and also by immunohistochemical study of multiple invasive prostate tumor markers. PSP-KIMAP model is responsive to androgen deprivation (castration). The knockin technology in our KIMAP model demonstrates highly predictive CaP development procedures and many advantageous features, which the traditional transgenic technique-derived CaP models could not reach for both basic and clinical studies. These features include the high stability of both phenotype and genotype, highly synchronous prostate cancer development, high and precise prostate tissue targeting and with no founder line variation. The differences between the two CaP models were attributed to the introduction of a single endogenous knockin mutation, resulting in a CaP model self-regulated and controlled by a prostate gene promoter/enhancer of PSP94.
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PMID:Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model. 1567 47

The transgenic adenocarcinoma mouse prostate (TRAMP) model, designed for researching human prostatic cancer, was genetically engineered to harbor a transgene composed of the simian virus 40 Large-T/small-t antigen promoted by the rat probasin gene. In addition to prostatic neoplasms, the TRAMP mouse develops tumors in the seminal vesicles. This study was conducted to evaluate the pathology and histogenesis of TRAMP seminal vesicle neoplasms. Tissues of accessory sex organs harvested from 72 TRAMP mice of various ages (11-40 weeks of age) were fixed in neutral buffered formalin and stained with hematoxylin and eosin, desmin, 5-bromo-2'-deoxyuridine (BrdU, treated animals only), and SV40 Large-T antigen (SV40-Tag). In the seminal vesicles, we found neoplastic stromal cells that emerged multicentrically just beneath the epithelium, densely packed between the epithelium and the smooth muscle layer. These stromal cells frequently exhibited mitotic figures and showed BrdU incorporation and SV40-Tag protein expression in the nuclei and immunopositivity for desmin. The proliferative mesenchymal cells were lined by cuboidal to columnar epithelium. Some of the larger papillary, polypoid lesions exhibited a phyllodes pattern resembling that seen in mixed epithelial-stromal tumors of the breast, prostate, and seminal vesicles of humans. Although the epithelium was negative for SV40-Tag and showed only occasional incorporation of BrdU, it clearly participated in the biphasic proliferation, forming papillary, cystic, and tubuloglandular structures. No conclusive evidence of malignancy (invasion or metastasis) was identified. Our recommended diagnosis of this lesion in the seminal vesicles is epithelial-stromal tumor.
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PMID:Epithelial-stromal tumor of the seminal vesicles in the transgenic adenocarcinoma mouse prostate model. 1587 76

The molecular mechanism(s) for prostate cancer progression to androgen independence are poorly understood. We have recently shown that Foxa1 and Foxa2 proteins are differentially expressed in epithelial cells during murine prostate development, growth, and adult function. Currently, the role of Foxa proteins in prostate cancer development and progression is unknown. Foxa protein expression was investigated in the LPB-Tag LADY mouse prostate cancer models, in human prostate cancer specimens, and various prostate cancer cell lines using Western blot and immunostaining analysis. In vitro transient transfection, studies were performed to investigate Foxa/prostate-specific gene regulation. Foxa1 was strongly expressed in areas of prostatic intraepithelial neoplasia (PIN) in both the androgen dependent 12T-7f and in the metastatic, androgen independent 12T-10 LADY models. Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice. Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas. Foxa proteins were also differentially expressed in three prostate cancer cell lines. Importantly, in vitro functional assays demonstrated that Foxa2 could activate androgen-dependent prostate-specific genes in an androgen receptor and ligand-independent manner. These results suggest that Foxa proteins are important in prostate carcinogenesis. In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence. As such, Foxa proteins may represent novel targets for therapeutic intervention.
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PMID:Expression and role of Foxa proteins in prostate cancer. 1600 49

Protein kinase C (PKC) isozymes, a family of serine-threonine kinases, are important regulators of cell proliferation and malignant transformation. Phorbol esters, the prototype PKC activators, cause PKC translocation to the plasma membrane in prostate cancer cells, and trigger an apoptotic response. Studies in recent years have determined that each member of the PKC family exerts different effects on apoptotic or survival pathways. PKCdelta, one of the novel PKCs, is a key player of the apoptotic response via the activation of the p38 MAPK pathway. Studies using RNAi revealed that depletion of PKCdelta totally abolishes the apoptotic effect of the phorbol ester PMA. Activation of the classical PKCalpha promotes the dephosphorylation and inactivation of the survival kinase Akt. Studies have assigned a pro-survival role to PKCepsilon, but the function of this PKC isozyme remains controversial. Recently, it has been determined that the PKC apoptotic effect in androgen-dependent prostate cancer cells is mediated by the autocrine secretion of death factors. PKCdelta stimulates the release of TNFalpha from the plasma membrane, and blockade of TNFalpha secretion or TNFalpha receptors abrogates the apoptotic response of PMA. Molecular analysis indicates the requirement of the extrinsic apoptotic cascade via the activation of death receptors and caspase-8. Dissecting the pathways downstream of PKC isozymes represents a major challenge to understanding the molecular basis of phorbol ester-induced apoptosis.
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PMID:Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells. 1633 77

Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism by which selenium inhibits carcinogenesis remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals: mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i6A-) and mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [C3(1)/Tag]. The resulting bigenic animals (i6A-/Tag) and control WT/Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia. The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.
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PMID:Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model. 1669 Jul 48

The effects of leuprorelin acetate, a luteinizing hormone-releasing hormone agonist (LHRH-A), on prostate carcinogenesis in probasin/SV40 Tag transgenic rat was investigated. Fifteen weeks after administration of 0.28 and 2.8 mg/kg leuprorelin, prostate weights and serum testosterone levels were significantly decreased compared to values for transgenic controls. Histopathological findings revealed that the incidence of prostatic adenocarcinomas was significantly reduced in ventral, dorsal and lateral lobes of the prostate, correlating with decreased expression of SV40 Tag oncoprotein as well as inhibition of DNA synthesis and proliferation of epithelial cells in neoplastic lesions of the ventral prostate. Microarray analysis further showed leuprorelin acetate to significantly inhibit testicular steroidogenesis, suppressing the expression of SV40 Tag oncoprotein and altering the expression of a large number of genes which might be involved in the inhibition of prostate cancer progression in this rat model.
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PMID:Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by leuprorelin, a luteinizing hormone-releasing hormone agonist. 1673 23

Rodents do not naturally develop prostate cancer. Currently, most widely used genetically engineered mouse prostate cancer models use SV40 T/tag oncogene. To understand the mechanism underlying prostate cancer development in transgenic and knock-in SV40 Tag mouse models, we did cDNA microarray analyses, comparing gene expression profiles of prostate cancer tissues from early-, late-, and advance-stage androgen-independent prostate cancers. Of the 67 genes that were up-regulated by > or = 10-fold, 40 are known to be required for chromosome stability. In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions. Significantly, Bub1, which is required for accurate chromosome segregation during mitosis, has recently been reported to bind SV40 Tag. Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation. Importantly, up-regulation and hyperphosphorylation of Bub1 were also observed in established human prostate cancer cell lines and in clinical studies. Furthermore, analysis of human prostate cancer lines showed impaired spindle checkpoint function and endoreduplication following exposure to spindle toxins. Small interfering RNA-mediated repression of Bub1 in the human prostate cancer line PC-3 restrained cell proliferation, an effect mimicked by inhibition of mitogen-activated protein kinase, an upstream activator of Bub1. Thus, by perturbing Bub1 function, our observations suggest a new mechanism whereby the SV40 Tag oncoprotein promotes chromosomal instability and aneuploidy in transgenic mouse prostate cancer models. Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America.
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PMID:Bub1 up-regulation and hyperphosphorylation promote malignant transformation in SV40 tag-induced transgenic mouse models. 1718 86

High dietary calcium has been shown in epidemiological studies to be a risk factor for prostate cancer, and it has been postulated that this effect is secondary to calcium induced modulation of the vitamin D axis. In this study, we used LPB-Tag transgenic mice on the CD1 background to examine the impact of dietary calcium on prostate tumor progression. CD1-LPB-Tag mice predictably develop autochthonous, hormone-responsive prostate tumors by 3 months of age. Age matched transgenic and non-transgenic littermates were weaned onto high (2%) or low (0.2%) calcium diets and mice were sacrificed at 5, 7, and 9 weeks of age. The entire urogenital complex was excised, weighed, and processed for histology. There was no significant effect of dietary calcium on tumor weight or on the time course of tumor progression, as monitored using a modified Gleason grade (MGS). Serum calcium was maintained in the normal range in mice on the low and high calcium diet throughout the study. Circulating 1,25(OH)(2)D(3) was elevated by low dietary calcium in 5-week-old mice, but not in older animals. In summary, neither development nor progression of prostate tumors in LPB-Tag mice was accelerated by high dietary calcium.
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PMID:Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. 1730 54

Transgenic (TG) rats bearing a probasin promoter/simian virus 40 T antigen (SV40 Tag) construct were treated with antiandrogens to examine their ability to suppress prostate carcinogenesis. Finasteride and flutamide were administered to 10-week-old TG rats five times a week for 2, 5 and 7 weeks. Antiandrogen-treated prostates exhibited atrophic glandular structures with almost no expression of SV40 Tag and only weak signals for androgen receptors. Furthermore, quantitative data for ventral prostate adenocarcinomas showed significant decrease with antiandrogen treatment. Both finasteride and flutamide had the ability to suppress SV40 Tag-driven carcinogenesis through their different antiandrogenic mechanisms, suggesting that this TG model is suitable for exploring the potential of agents to inhibit prostate cancer development.
Prostate Cancer Prostatic Dis 2007
PMID:Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model. 1745 4

New therapeutic agents are needed for the treatment of androgen-independent prostate cancer (PrCa). We have investigated the effect of methylseleninic acid (MSA) on tumor stage-specific prostate cells derived from the C3 (1)/Tag model for PrCa: Pr111, a slow-growing and nontumorigenic cell line isolated from a prostate intraepithelial neoplasia lesion; Pr14, a tumorigenic line derived from a primary tumor; and Pr14C1, a sub-clone of Pr14 explanted from a lung metastasis. We demonstrate that MSA strongly inhibits cell growth and induces apoptosis in C3 (1)/Tag tumor cells, in a dose-dependent manner. A decrease in phosphorylated ERK1/2 and AKT was also found in tumor cells, but not in Pr111. Microarray analysis using affymetrix showed that the number of genes with an altered expression in tumor cells is significantly higher (p < 0.01) than in nontumoral cells. Pathways analyses revealed a decrease in the expression of genes involved in metabolism (Fabp5, Cyba), signal transduction (ERK, AKT), angiogenesis (neuropilin-1, Flt-4) and transcription (cAMP response element-binding protein) in tumor cells. The expression of neuropilin-1, a protein involved in VEGF signaling and tumor angiogenesis, was 97-fold repressed in Pr14 cells treated with MSA. Combination treatments using low doses of etoposide or taxotere (docetaxel), plus low doses of MSA revealed a strong enhancement of cell growth inhibition and apoptosis in tumor cells. Our in vivo studies using Pr14 cells xenografted into nude mice demonstrated that MSA significantly enhances the chemotherapeutical effect of etoposide, resulting in 78.3% tumor growth inhibition. These results suggest that MSA could be used against PrCa to enhance the effect of etoposide.
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PMID:Methylseleninic acid enhances the effect of etoposide to inhibit prostate cancer growth in vivo. 1752 Jun 73


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