The Experts below are selected from a list of 1191 Experts worldwide ranked by ideXlab platform
Robert J Matusik - One of the best experts on this subject based on the ideXlab platform.
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Foxa2 activates the transcription of androgen receptor target genes in castrate resistant prostatic tumors.
American journal of clinical and experimental urology, 2018Co-Authors: Zachary M. Connelly, Shu Yang, Fenghua Chen, Yunshin Yeh, Nazih Khater, Renjie Jin, Robert J MatusikAbstract:Prostate cancer (PCa) is the leading cancer among men. Androgen Deprivation Therapy (ADT) is a common treatment for advanced PCa. However, ADT eventually fails and PCa relapses, developing into castration-resistant prostate cancer (CRPCa). Although alternative pathways such as cancer stem-cell pathway and neuroendocrine differentiation bypass androgen receptor (AR) signaling, AR remains the central player in mediating CRPCa. In this study, we identified a mechanism that retains AR signaling after androgen deprivation. The TRAMP SV40 T antigen transgenic mouse is a model for PCa. The expression of SV40 T-antigen is driven by the androgen-responsive, prostate specific, Probasin promoter. It has been recognized that in this model, T-antigen is still expressed even after androgen ablation. It is unclear how the androgen-responsive Probasin promoter remains active and drives the expression of T-antigen in these tumors. In our study, we found that the expression of Foxa2, a forkhead transcription factor that is expressed in embryonic prostate and advanced stage prostate cancer, is co-expressed in T-antigen positive cells. To test if Foxa2 activates AR-responsive promoters and promotes the expression of T-antigen, we established the prostate epithelial cells that stably express Foxa2, NeoTag1/Foxa2 cells. Neotag1 cells were derived from the Probasin promoter driven SV40 T-antigen transgenic mouse. We found ectopic expression of Foxa2 drives the T-antigen expression regardless of the presence of androgens. Using this model system, we further explored the mechanism that activates AR-responsive promoters in the absence of androgens. Chromatin immunoprecipitation revealed the occupancy of both H3K27Ac, an epigenetic mark of an active transcription, and Foxa2 at the known AR target promoters, Probasin and FKBP5, in the absence of androgen stimulation. In conclusion, we have identified a mechanism that enables PCa to retain the AR signaling pathway after androgen ablation.
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Fibroblast Growth Factor 8 Isoform b Overexpression in Prostate Epithelium: A New Mouse Model for Prostatic Intraepithelial Neoplasia 1
2013Co-Authors: Zhigang Song, Robert J Matusik, Robert D. Cardiff, William C. Powell, Michael B. Cohen, Robert T. Tin, Gary J. Miller, Pradip Roy-burmanAbstract:Fibroblast growth factor 8 isoform b (FGF8b), a mitogenic and transforming polypeptide, was demonstrated to be naturally up-regulated in prostatic premalignant and malignant lesions in men. We generated four independent lines of transgenic mice with targeted overexpression of FGF8b in the prostatic epithelium using an improved rat Probasin promoter, ARR 2PB. Transgene expression in the prostate tissue was readily demonstrated by reverse transcription-PCR and localized to the prostatic epithelium by in situ hybridization. The histopathology of the prostate tissues was followed in different age groups of the various lines but most extensively in one line (line 3), starting from 1 month of age up to 24 months. Prostatic hyperplasia appeared in the lateral and ventral prostates in some animals as early as 2–3 months and in other lobes between 6 and 16 months. Beginning at 5–7 months, dysplasia, akin to what may be considered low-grade prostatic intraepithelial neoplasia (LGPIN) in humans
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Printed in U.S.A. Copyright © 2000 by The Endocrine Society A Small Composite Probasin Promoter Confers High Levels of Prostate-Specific Gene Expression through Regulation by Androgens and Glucocorticoids in Vitro and in Vivo*
2013Co-Authors: Jianfeng Zhang, Tania Z Thomas, Susan Kasper, Robert J MatusikAbstract:Transient transfection studies have shown that the Probasin (PB) promoter confers androgen selectivity over other steroid hormones, and transgenic animal studies have demonstrated that the PB promoter will target androgen, but not glucocorticoid, regulation in a prostate-specific manner. Previous PB promoters either targeted low levels of transgene expression or became too large to be conveniently used. The goal was to design a PB promoter that would be small, yet target high levels of prostate-specific transgene expression. Thus, a composite Probasin promoter (ARR 2PB) coupled to the bacterial chloramphenicol acetyltransferase reporter (ARR 2PBCAT) was generated and tested in prostatic and nonprostatic cell lines and in a transgenic mouse model. In PC-3, LNCaP, and DU145 prostate cancer cell lines, the ARR 2PB promoter gave basal expression and was induced in response to androgen and glucocorticoid treatment after cotransfectio
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ARF represses androgen receptor transactivation in prostate cancer.
Molecular endocrinology (Baltimore Md.), 2013Co-Authors: Yingqiu Xie, Robert J Matusik, Zhenbang ChenAbstract:Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of AR activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with AR and functions as an AR corespressor in both an androgen-dependent and androgen-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and AR colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-Probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor l...
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characterization of cis elements of the Probasin promoter necessary for prostate specific gene expression
The Prostate, 2010Co-Authors: Jianfeng Zhang, Susan Kasper, Thomas C. Case, Nan Gao, David J. Degraff, Qian Sun, Robert J MatusikAbstract:BACKGROUND The androgen-regulated Probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a “pioneer factor” that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (−244/−96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression. Prostate 70: 934–951, 2010. © 2010 Wiley-Liss, Inc.
Tomoyuki Shirai - One of the best experts on this subject based on the ideXlab platform.
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Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.
The Prostate, 2009Co-Authors: Curt E. Harper, Tomoyuki Shirai, Leah M. Cook, Brijesh B. Patel, Jun Wang, Isam A. Eltoum, Ali Arabshahi, Coral A. LamartiniereAbstract:Background Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted Probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer.
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disruption of growth hormone signaling retards prostate carcinogenesis in the Probasin tag rat
Endocrinology, 2008Co-Authors: Zhuohua Wang, Tomoyuki Shirai, Raúl M. Luque, Rhonda D. Kineman, Vera Ray, Konstantin Christov, Daniel D. Lantvit, Samad Hedayat, Terry G. UntermanAbstract:We asked whether down-regulation of GH signaling could block carcinogenesis in the Probasin/TAg rat, a model of aggressive prostate cancer. The Spontaneous Dwarf rat, which lacks GH due to a mutation (dr) in its GH gene, was crossed with the Probasin/TAg rat, which develops prostate carcinomas at 100% incidence by 15 wk of age. Progeny were heterozygous for the TAg oncogene and homozygous for either the wild-type GH gene (TAg/Gh(+/+)) or the dr mutation (TAg/Gh(dr/dr)). Prostate tumor incidence and burden were significantly reduced, and tumor latency was delayed in TAg/Gh(dr/dr) rats relative to TAg/Gh(+/+) controls. At 25 wk of age, loss of GH resulted in a 20 and 80% decrease in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 wk of age, invasive prostate adenocarcinomas were observed in all TAg/Gh(+/+) rats, whereas the majority of TAg/Gh(dr/dr) did not develop invasive tumors. Suppression of carcinogenesis could not be attributed to alterations in prostate expression of TAg or androgen receptor or changes in serum testosterone levels. As carcinogenesis progressed in TAg/Gh(+/+) rats, prostate GHR mRNA and protein expression increased significantly, but prostate IGF-I receptor mRNA and protein levels dropped. Furthermore, serum IGF-I and prostate IGF-I levels did not change significantly over the course of carcinogenesis. These findings suggest that GH plays a dominant role in progression from latent to malignant prostate cancer driven by the powerful Probasin/TAg fusion gene in rats and suggest that GH antagonists may be effective at treating human prostate cancer.
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Suppression of Prostate Cancer Growth by Resveratrol in The Transgenic Rat for Adenocarcinoma of Prostate (TRAP) Model
Asian Pacific journal of cancer prevention : APJCP, 2008Co-Authors: Azman Seeni, Mingxi Tang, Satoru Takahashi, Kentaro Takeshita, Satoshi Sugiura, Shinya Sato, Tomoyuki ShiraiAbstract:Research into actions of resveratrol, abundantly present in red grape skin, has been greatly stimulated by its reported beneficial health influence. Since it was recently proposed as a potential prostate cancer chemopreventive agent, we here performed an in vivo experiment to explore its effect in the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model, featuring the rat Probasin promoter/SV 40 T antigen. Resveratrol suppressed prostate cancer growth and induction of apoptosis through androgen receptor (AR) down-regulation, without any sign of toxicity. Resveratrol not only downregulated androgen receptor (AR) expression but also suppressed the androgen responsive glandular kallikrein 11 (Gk11), known to be an ortholog of the human prostate specific antigen (PSA), at the mRNA level. The data provide a mechanistic basis for resveratrol chemopreventive efficacy against prostate cancer.
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Disruption of Growth Hormone Signaling Retards Prostate Carcinogenesis in the Probasin/TAg Rat
Endocrinology, 2007Co-Authors: Zhuohua Wang, Tomoyuki Shirai, Raúl M. Luque, Rhonda D. Kineman, Vera Ray, Konstantin Christov, Daniel D. Lantvit, Samad Hedayat, Terry G. Unterman, Maarten C. BoslandAbstract:We asked whether down-regulation of GH signaling could block carcinogenesis in the Probasin/TAg rat, a model of aggressive prostate cancer. The Spontaneous Dwarf rat, which lacks GH due to a mutation (dr) in its GH gene, was crossed with the Probasin/TAg rat, which develops prostate carcinomas at 100% incidence by 15 wk of age. Progeny were heterozygous for the TAg oncogene and homozygous for either the wild-type GH gene (TAg/Gh(+/+)) or the dr mutation (TAg/Gh(dr/dr)). Prostate tumor incidence and burden were significantly reduced, and tumor latency was delayed in TAg/Gh(dr/dr) rats relative to TAg/Gh(+/+) controls. At 25 wk of age, loss of GH resulted in a 20 and 80% decrease in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 wk of age, invasive prostate adenocarcinomas were observed in all TAg/Gh(+/+) rats, whereas the majority of TAg/Gh(dr/dr) did not develop invasive tumors. Suppression of carcinogenesis could not be attributed to alterations in prostate expression of TAg or androgen receptor or changes in serum testosterone levels. As carcinogenesis progressed in TAg/Gh(+/+) rats, prostate GHR mRNA and protein expression increased significantly, but prostate IGF-I receptor mRNA and protein levels dropped. Furthermore, serum IGF-I and prostate IGF-I levels did not change significantly over the course of carcinogenesis. These findings suggest that GH plays a dominant role in progression from latent to malignant prostate cancer driven by the powerful Probasin/TAg fusion gene in rats and suggest that GH antagonists may be effective at treating human prostate cancer.
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Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model
Prostate cancer and prostatic diseases, 2007Co-Authors: Young-man Cho, Mingxi Tang, Shugo Suzuki, Makoto Asamoto, Satoru Takahashi, Tomoyuki ShiraiAbstract: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.
Susan Kasper - One of the best experts on this subject based on the ideXlab platform.
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Corresponding Author:
2016Co-Authors: Pierre Chaur, Susan Kasper, Richard M Caprioli, Mohammed A. Rahman, Tamela Hunt, James A. Mobley, Joey C. LathamAbstract:Mass spectrometry-based tissue profiling and imaging are technologies which allow identification and visualization of protein signals directly on thin sections cut from fresh frozen tissue specimens. These technologies were utilized to evaluate protein expression profiles in the normal mouse prostate during development (1 to 5 weeks of age), sexual maturation (6 weeks of age) and adult prostate (at 10, 15 or 40 weeks of age). The evolution of protein expression during normal prostate development and maturation were subsequently compared to 15 week prostate tumors derived from genetically engineered mice carrying the Large T antigen gene under regulation of the prostate-specific Probasin promoter (LPB-Tag mouse model for prostate cancer). This approach identified proteins differentially expressed at specific time points during prostate development. Furthermore, expression of some of these proteins, for example Probasin and spermine binding protein, were associated with prostate maturation, and prostate tumor formation resulted in their loss of expression. Cyclophilin A, a protein found in other cancers, was differentially α-acetylated on the N-terminal and both isoforms appeared during normal prostate and prostate tumor development. Imaging mass spectrometry localized the protein signals to specific prostatic lobes or regions. Thus, tissue profiling and imaging can be utilized t
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Printed in U.S.A. Copyright © 2000 by The Endocrine Society A Small Composite Probasin Promoter Confers High Levels of Prostate-Specific Gene Expression through Regulation by Androgens and Glucocorticoids in Vitro and in Vivo*
2013Co-Authors: Jianfeng Zhang, Tania Z Thomas, Susan Kasper, Robert J MatusikAbstract:Transient transfection studies have shown that the Probasin (PB) promoter confers androgen selectivity over other steroid hormones, and transgenic animal studies have demonstrated that the PB promoter will target androgen, but not glucocorticoid, regulation in a prostate-specific manner. Previous PB promoters either targeted low levels of transgene expression or became too large to be conveniently used. The goal was to design a PB promoter that would be small, yet target high levels of prostate-specific transgene expression. Thus, a composite Probasin promoter (ARR 2PB) coupled to the bacterial chloramphenicol acetyltransferase reporter (ARR 2PBCAT) was generated and tested in prostatic and nonprostatic cell lines and in a transgenic mouse model. In PC-3, LNCaP, and DU145 prostate cancer cell lines, the ARR 2PB promoter gave basal expression and was induced in response to androgen and glucocorticoid treatment after cotransfectio
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characterization of cis elements of the Probasin promoter necessary for prostate specific gene expression
The Prostate, 2010Co-Authors: Jianfeng Zhang, Susan Kasper, Thomas C. Case, Nan Gao, David J. Degraff, Qian Sun, Robert J MatusikAbstract:BACKGROUND The androgen-regulated Probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a “pioneer factor” that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (−244/−96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression. Prostate 70: 934–951, 2010. © 2010 Wiley-Liss, Inc.
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Characterization of cis elements of the Probasin promoter necessary for prostate‐specific gene expression
The Prostate, 2010Co-Authors: Jianfeng Zhang, Susan Kasper, Thomas C. Case, Nan Gao, David J. Degraff, Qian Sun, Robert J MatusikAbstract:BACKGROUND The androgen-regulated Probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a “pioneer factor” that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (−244/−96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression. Prostate 70: 934–951, 2010. © 2010 Wiley-Liss, Inc.
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Monitoring Mouse Prostate Development by Profiling and Imaging Mass Spectrometry
Molecular & cellular proteomics : MCP, 2007Co-Authors: Pierre Chaurand, Richard M Caprioli, Mohammed A. Rahman, Tamela Hunt, James A. Mobley, Joey C. Latham, Susan KasperAbstract:Mass spectrometry-based tissue profiling and imaging are technologies that allow identification and visualization of protein signals directly on thin sections cut from fresh frozen tissue specimens. These technologies were utilized to evaluate protein expression profiles in the normal mouse prostate during development (1-5 weeks of age), at sexual maturation (6 weeks of age), and in adult prostate (at 10, 15, or 40 weeks of age). The evolution of protein expression during normal prostate development and maturation were subsequently compared with 15-week prostate tumors derived from genetically engineered mice carrying the Large T antigen gene under regulation of the prostate-specific Probasin promoter (LPB-Tag mouse model for prostate cancer). This approach identified proteins differentially expressed at specific time points during prostate development. Furthermore expression of some of these proteins, for example Probasin and spermine-binding protein, were associated with prostate maturation, and prostate tumor formation resulted in their loss of expression. Cyclophilin A, a protein found in other cancers, was differentially alpha-acetylated on the N terminus, and both isoforms appeared during normal prostate and prostate tumor development. Imaging mass spectrometry localized the protein signals to specific prostatic lobes or regions. Thus, tissue profiling and imaging can be utilized to analyze the ontogeny of protein expression during prostate morphogenesis and tumorigenesis and identify proteins that could potentially serve as biomarkers for prostate cancer.
Makoto Asamoto - One of the best experts on this subject based on the ideXlab platform.
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Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model
Prostate cancer and prostatic diseases, 2007Co-Authors: Young-man Cho, Mingxi Tang, Shugo Suzuki, Makoto Asamoto, Satoru Takahashi, Tomoyuki ShiraiAbstract: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.
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inhibition of prostate carcinogenesis in Probasin sv40 t antigen transgenic rats by leuprorelin a luteinizing hormone releasing hormone agonist
Cancer Science, 2006Co-Authors: Mahmoud M Said, Naomi Hokaiwado, Mingxi Tang, Kumiko Ogawa, Shugo Suzuki, Hala M Ghanem, Amr Y Esmat, Makoto Asamoto, Fawzia M RefaieAbstract: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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Inhibition of prostate carcinogenesis in Probasin/SV40 T antigen transgenic rats by leuprorelin, a luteinizing hormone-releasing hormone agonist.
Cancer science, 2006Co-Authors: Mahmoud M Said, Naomi Hokaiwado, Mingxi Tang, Kumiko Ogawa, Shugo Suzuki, Hala M Ghanem, Amr Y Esmat, Makoto Asamoto, Fawzia M Refaie, Tomoyuki ShiraiAbstract: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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lack of effect of human c ha ras proto oncogene overexpression on prostate carcinogenesis in Probasin sv40 t antigen transgenic rats
Cancer Science, 2003Co-Authors: Naomi Hokaiwado, Makoto Asamoto, Young-man Cho, Hiroyuki Tsuda, Tomoyuki ShiraiAbstract:We have previously reported that transgenic (Tg) rats bearing the SV40 T antigen under Probasin promoter control (PB/SV40T) develop prostate carcinomas at 100% incidence, showing their prostate carcinoma growth to be completely androgen-dependent. Transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are also highly susceptible to carcinogen induction of multiple mammary carcinomas, in this case estrogen-independent, since ovariectomy does not affect mammary tumor formation. A relationship between ras/mitogen-activated protein kinase signaling and androgen responsiveness of prostate cancer cells has been reported. Therefore it is of interest to investigate whether expression of human c-Ha-ras affects the androgen-dependence of prostate carcinomas developing in the PB/SV40T Tg rat. For this purpose, we established double transgenic (rasTag) rats bearing both PB/SV40T and Hras128. In prostate tissues of the rasTag rats, expression of both human c-Ha-ras and SV40T was confirmed, but the prostate tumor incidence and growth were not significantly affected. Castration at 15 weeks of age induced complete tumor involution in the rasTag rats. These results indicate that the human c-Ha-ras proto-oncogene product does not influence the androgen-dependence of prostate carcinogenesis due to the Probasin-mediated SV40 T antigen, despite the estrogen-independence of mammary carcinogenesis in Hras128 rats.
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age dependent histopathological findings in the prostate of Probasin sv40 t antigen transgenic rats lack of influence of carcinogen or testosterone treatment
Cancer Science, 2003Co-Authors: Young-man Cho, Naomi Hokaiwado, Shugo Suzuki, Makoto Asamoto, Satoru Takahashi, Shingo Inaguma, Tomoyuki ShiraiAbstract:Sequential changes in the phenotype of prostatic lesions and the impact of additional carcinogen treatment or castration on development and progression of prostate cancers were examined in Probasin/simian virus 40 (SV40) T antigen transgenic (TG) rats. Non-invasive prostate adenocarcinomas were evident in all lobes at 15 weeks of age. Invasive tumors were limited to the anterior lobe at this time point and were found in all lobes in an age-dependent manner thereafter. No metastasis was apparent at any age. Additional carcinogen treatment or castration did not enhance progression or generate selective growth of hormone-independent prostate cancer cells. These results suggest that our TG rats are suitable for clarification of mechanisms in early stages of prostate carcinogenesis, that is, from prostatic intraepithelial neoplasia (PIN) to non-invasive and then invasive lesions.
Young-man Cho - One of the best experts on this subject based on the ideXlab platform.
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Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model
Prostate cancer and prostatic diseases, 2007Co-Authors: Young-man Cho, Mingxi Tang, Shugo Suzuki, Makoto Asamoto, Satoru Takahashi, Tomoyuki ShiraiAbstract: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.
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lack of effect of human c ha ras proto oncogene overexpression on prostate carcinogenesis in Probasin sv40 t antigen transgenic rats
Cancer Science, 2003Co-Authors: Naomi Hokaiwado, Makoto Asamoto, Young-man Cho, Hiroyuki Tsuda, Tomoyuki ShiraiAbstract:We have previously reported that transgenic (Tg) rats bearing the SV40 T antigen under Probasin promoter control (PB/SV40T) develop prostate carcinomas at 100% incidence, showing their prostate carcinoma growth to be completely androgen-dependent. Transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are also highly susceptible to carcinogen induction of multiple mammary carcinomas, in this case estrogen-independent, since ovariectomy does not affect mammary tumor formation. A relationship between ras/mitogen-activated protein kinase signaling and androgen responsiveness of prostate cancer cells has been reported. Therefore it is of interest to investigate whether expression of human c-Ha-ras affects the androgen-dependence of prostate carcinomas developing in the PB/SV40T Tg rat. For this purpose, we established double transgenic (rasTag) rats bearing both PB/SV40T and Hras128. In prostate tissues of the rasTag rats, expression of both human c-Ha-ras and SV40T was confirmed, but the prostate tumor incidence and growth were not significantly affected. Castration at 15 weeks of age induced complete tumor involution in the rasTag rats. These results indicate that the human c-Ha-ras proto-oncogene product does not influence the androgen-dependence of prostate carcinogenesis due to the Probasin-mediated SV40 T antigen, despite the estrogen-independence of mammary carcinogenesis in Hras128 rats.
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age dependent histopathological findings in the prostate of Probasin sv40 t antigen transgenic rats lack of influence of carcinogen or testosterone treatment
Cancer Science, 2003Co-Authors: Young-man Cho, Naomi Hokaiwado, Shugo Suzuki, Makoto Asamoto, Satoru Takahashi, Shingo Inaguma, Tomoyuki ShiraiAbstract:Sequential changes in the phenotype of prostatic lesions and the impact of additional carcinogen treatment or castration on development and progression of prostate cancers were examined in Probasin/simian virus 40 (SV40) T antigen transgenic (TG) rats. Non-invasive prostate adenocarcinomas were evident in all lobes at 15 weeks of age. Invasive tumors were limited to the anterior lobe at this time point and were found in all lobes in an age-dependent manner thereafter. No metastasis was apparent at any age. Additional carcinogen treatment or castration did not enhance progression or generate selective growth of hormone-independent prostate cancer cells. These results suggest that our TG rats are suitable for clarification of mechanisms in early stages of prostate carcinogenesis, that is, from prostatic intraepithelial neoplasia (PIN) to non-invasive and then invasive lesions.
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Lack of effect of human c-Ha-ras proto-oncogene overexpression on prostate carcinogenesis in Probasin/SV40 T antigen transgenic rats.
Cancer science, 2003Co-Authors: Naomi Hokaiwado, Makoto Asamoto, Young-man Cho, Hiroyuki Tsuda, Tomoyuki ShiraiAbstract:We have previously reported that transgenic (Tg) rats bearing the SV40 T antigen under Probasin promoter control (PB/SV40T) develop prostate carcinomas at 100% incidence, showing their prostate carcinoma growth to be completely androgen-dependent. Transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are also highly susceptible to carcinogen induction of multiple mammary carcinomas, in this case estrogen-independent, since ovariectomy does not affect mammary tumor formation. A relationship between ras/mitogen-activated protein kinase signaling and androgen responsiveness of prostate cancer cells has been reported. Therefore it is of interest to investigate whether expression of human c-Ha-ras affects the androgen-dependence of prostate carcinomas developing in the PB/SV40T Tg rat. For this purpose, we established double transgenic (rasTag) rats bearing both PB/SV40T and Hras128. In prostate tissues of the rasTag rats, expression of both human c-Ha-ras and SV40T was confirmed, but the prostate tumor incidence and growth were not significantly affected. Castration at 15 weeks of age induced complete tumor involution in the rasTag rats. These results indicate that the human c-Ha-ras proto-oncogene product does not influence the androgen-dependence of prostate carcinogenesis due to the Probasin-mediated SV40 T antigen, despite the estrogen-independence of mammary carcinogenesis in Hras128 rats.
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Age-dependent histopathological findings in the prostate of Probasin/SV40 T antigen transgenic rats: lack of influence of carcinogen or testosterone treatment.
Cancer science, 2003Co-Authors: Young-man Cho, Naomi Hokaiwado, Shugo Suzuki, Makoto Asamoto, Satoru Takahashi, Shingo Inaguma, Tomoyuki ShiraiAbstract:Sequential changes in the phenotype of prostatic lesions and the impact of additional carcinogen treatment or castration on development and progression of prostate cancers were examined in Probasin/simian virus 40 (SV40) T antigen transgenic (TG) rats. Non-invasive prostate adenocarcinomas were evident in all lobes at 15 weeks of age. Invasive tumors were limited to the anterior lobe at this time point and were found in all lobes in an age-dependent manner thereafter. No metastasis was apparent at any age. Additional carcinogen treatment or castration did not enhance progression or generate selective growth of hormone-independent prostate cancer cells. These results suggest that our TG rats are suitable for clarification of mechanisms in early stages of prostate carcinogenesis, that is, from prostatic intraepithelial neoplasia (PIN) to non-invasive and then invasive lesions.