| Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy |
Jul-2009 |
12 pages |
| Authors:
Diane M Robins; MICHIGAN UNIV ANN ARBOR
|
 | In mice in which human androgen receptor (AR) replaces the endogenous murine gene, variation in the length of a polymorphic N-terminal polyglutamine tract affects initiation, progression and therapy response prostate tumors. This provides a genetic paradigm in which to dissect AR functions that determine response to therapy. We are studying the role of the AR Q tract in ligand-independent AR activation in vitro and in a mouse model with prostate ... |
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| A Novel Anti-Beta2-Microglobulin Antibody Inhibition of Androgen Receptor Expression, Survival, and Progression in Prostate Cancer Cells |
31-May-2009 |
21 pages |
| Authors:
Wen-Chin Huang; EMORY UNIV ATLANTA GA
|
| Beta2-microglobulin (beta2M) is a signaling and growth-promoting factor stimulating prostate cancer cell proliferation and progression. Blockade of the beta2M signaling axis resulted in the inhibition of androgen receptor (AR) and its target gene, prostate-specific antigen (PSA), and the induction of programmed death of prostate cancer cells through activation of a caspase-dependent pathway in vitro and in vivo. In this annual summary report, we identified a cis-acting element, sterol regulatory element-binding ... |
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| Obstructing Androgen Receptor Activation in Prostate Cancer Cells through Posttranslational Modification by NEDD8 |
May-2009 |
6 pages |
| Authors:
Chen; D J; ROBERT WOOD JOHNSON MEDICAL SCHOOL PISCATAWAY NJ
|
| In this study, we aim to investigate post-translational modification of the androgen receptor (AR) by a small ubiquitin-like protein, Nedd8. We planned to analyze the consequence of Nedd8 modification on AR activity, and to identify the neddylation sites on AR. We also planned to determine enzymes involved in AR neddylation and de-neddylation. We have completed all proposed tasks in the first year. Key accomplishments so far include the development of ... |
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| Investigating the Role of TBX2 in the Inhibition of Senescence in Prostate Cancer |
01-Mar-2009 |
11 pages |
| Authors:
Srinivas Nandana; VANDERBILT UNIV NASHVILLE TN
|
| The aim of this project is to dissect the role of Tbx2 in prostate cancer progression. In this period of the study, we found that blocking endogenous Tbx2 expression in PC3 cells by using a dominant negative construct (PC3-Tbx2 DN) reduced the osteolytic burden of these cells when placed in the bone microenvironment as compared to control PC3 cells. This finding suggests that Tbx2 plays a role in the growth ... |
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| TAF1, From a General Transcription Factor to Modulator of Androgen Receptor in Prostate Cancer |
Feb-2009 |
16 pages |
| Authors:
Peyman Tavassoli; Paul Rennie; BRITISH COLUMBIA UNIV VANCOUVER
|
| The androgen receptor (AR) is a ligand-activated transcription factor that is essential for development and progression of prostate cancer. Using the N-terminus of AR as bait in the repressed transactivator yeast two-hybrid system, TATA binding protein-associated factor 1 (TAF1) was identified. TAF1, a multifunctional protein that contains acetylation, ubiquitin activating and kinase domains, can interact with several proteins to promote or suppress gene transcription. In the present study, using GST ... |
|
| A Novel Mechanism of Androgen Receptor Action |
01-Jan-2009 |
46 pages |
| Authors:
Roberts; Charles T Jr; OREGON HEALTH AND SCIENCES UNIV PORTLAND
|
| This revised project had as its goal the characterization of a novel alternative product of the Her-2/neu/erbB2 protooncogene derived from intron retention. The product of this splicing mechanism, termed herstatin, is a secreted protein comprised of the N terminus of the Her-2 receptor tyrosine kinase and a unique, intron-encoded C terminus that allows binding to the other members of the EGFR/erbB family. This binding down-regulates erbB expression and inhibits EGF ... |
|
| Biological Impact of Senescence Induction in Prostate Cancer Therapy |
Jan-2009 |
48 pages |
| Authors:
David F Jarrard; WISCONSIN UNIV-MADISON
|
| Recently, it has been recognized that a distinct mechanism of terminal proliferation arrest after chemotherapy involves the reactivation of senescence. However, whether this phenotype occurs in vivo is unclear, as is the biological impact of senescence induction. We have previously identified pathways and genes involved in human senescence that may serve as senescence markers, and have demonstrated that senescence occurs in prostate cancer cell lines after chemotherapy. In this proposal, ... |
|
| The Function of PTP1B in Neuroendocrine Differentation of Prostate Cancer |
Jan-2009 |
37 pages |
| Authors:
Jiaoti Huang; ROCHESTER UNIV NY
|
| The goal of the project is to identify the molecular mechanisms responsible for therapeutic failure in prostate cancer patients receiving hormonal therapy Scope: The scope of the project is to use prostate cancer cell lines in in-vitro cell culture systems to study the complex signal transduction pathways that may be responsible for the neuroendocrine differentiation of prostate cancer cells, particularly the relationship of PTP1B to IL-8 signaling through its receptors ... |
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| Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators |
Jan-2009 |
34 pages |
| Authors:
Clementine Feau; SAINT JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN
|
| Androgens, mediated by the Androgen Receptor (AR), play a crucial role in prostate cancer. Current treatments are focused on anti-androgenic drugs competing with natural androgens and antagonizing the transcriptional activity of the AR. Although widely used, these drugs have shown significant side effects and in addition, tumors have become resistant suggesting mutations of the receptor. Regulation of gene expression by AR requires the binding to androgens or to its natural ... |
|
| Involvement of Novel Multifunction Steroid Hormone Receptor Coactivator, E6-Associated Protein, in Prostate Gland Tumorigenesis |
Jan-2009 |
18 pages |
| Authors:
Sathish Srinivasan; MIAMI UNIV FL
|
| E3 ubiquitin-protein ligase enzyme, E6-associated protein (E6-AP), is a novel dual function steroid hormone receptor coactivator. Previously I have shown that E6-AP regulates PI3K-Akt pathway in the prostate gland and as well as LNCaP cells. In this report I have provided evidence that E6-AP plays a vital role in the prostate gland growth and prostate cancer cell proliferation. E6-AP by itself can modulate p53 levels in prostate cancer cells independent ... |
|
| Inhibitors for Androgen Receptor Activation Surfaces |
Sep-2008 |
8 pages |
| Authors:
Robert J Fletterick; CALIFORNIA UNIV SAN FRANCISCO
|
| Our research demonstrated a new protein interaction site on the androgen receptor. We showed that the site called BF3 has the characteristics of functioning in repression and likely binds one or more proteins. We are presently performing experiments to identify these proteins. We used X-ray crystallography to learn the binding mode of small molecule compounds that bind to this site. The BF3 site is allosteric because binding is accompanied by ... |
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| Changes in Ovarian Stromal Function and Associated Symptoms in Premenopausal Women Undergoing Chemotherapy for Breast Cancer |
Aug-2008 |
17 pages |
| Authors:
Marlene H Frost; MAYO CLINIC ROCHESTER MN
|
| The objective of this pilot study was to identify if androgen levels are adversely affected by adjuvant chemotherapy for breast cancer and whether low androgen levels are correlated with the frequency and severity of fatigue, weight gain, psychological symptoms, vasomotor symptoms and libido. A longitudinal, descriptive design was used with questionnaires completed and blood drawn from 20 premenopausal women at 4 time periods: before treatment, mid-treatment, immediate post-treatment and 6 ... |
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| Role of Hsp90 in Androgen-Refractory Prostate Cancer |
01-Mar-2008 |
8 pages |
| Authors:
Zhou Wang; PITTSBURGH UNIV PA
|
| A major challenge in prostate cancer research is to develop novel therapies that can delay or prevent the progression of androgen-sensitive prostate cancer to androgen-independence. Androgen receptor (AR) is often overexpressed and plays an essential role in androgen-refractory prostate tumors. Our preliminary studies suggest that heat shock protein 90 (Hsp90) is required for androgen-independent AR nuclear localization in androgen-refractory prostate cancer cells. This project will test our research hypothesis that ... |
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| CHD8, A Novel Beta-Catenin Associated Chromatin Remodeling Enzyme, Regulates Androgen Receptor Mediated Gene Transcription |
01-Mar-2008 |
7 pages |
| Authors:
Daniel A Bochar; MICHIGAN UNIV ANN ARBOR
|
| The activity of the androgen receptor (AR) is critical for normal prostate development and function, but AR activity also plays a major role in the development and progression of prostate cancer. To better understand the function of beta-catenin in AR mediated transcription, we have identified a novel chromatin remodeling enzyme, CHD8, that can associate with beta-catenin and functions in AR mediated gene transcription. Year 1 was focused on the first ... |
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| Identify the Impact of TGF-Beta Signaling on the Stroma in the Progression of Prostate Cancer |
01-Mar-2008 |
12 pages |
| Authors:
Neil A Bhowmick; VANDERBILT UNIV NASHVILLE TN
|
| As a result of androgen ablation TGF- 1 expression levels transiently elevate and regression of benign prostate hyperplasia as well as prostate cancer cells for the most part occur. Better understanding of prostate androgen responsiveness is critical in understanding and ultimately combating androgen-non-responsive prostate cancer. Studying the conditional TGF- type II receptor fibroblast knockout mouse model we developed (F KO), we found that TGF- signaling in the prostate stromal fibroblasts ... |
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| Inhibition of Androgen-Independent Growth of Prostate Cancer by siRNA- Mediated Androgen Receptor Gene Silencing |
01-Feb-2008 |
102 pages |
| Authors:
Benyi Li; KANSAS UNIV MEDICAL CENTER KANSAS CITY
|
| To determine if AR gene silencing in prostate cancer cells via RNA interference mechanism leads to disruption of androgen-independent progression. We generated a recombinant AAV for long-term expression of a hairpin-structured AR siRNA in vivo. Then we determined the essential role of the androgen receptor in androgen-independent growth of prostate cancer. We demonstrated that knocking down AR expression abolished tumor growth and blocked androgen-independent transition in LNCaP and LAPC-4 cell-derived ... |
|
| Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators |
31 JAN 2008 |
21 pages |
| Authors:
Clementine Feau; SAINT JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN
|
| Androgens, mediated by the Androgen Receptor (AR), play a crucial role in prostate cancer. Current treatments include antiandrogens competing with natural androgens and antagonize AR transcriptional activity. Although widely used, antiandrogens have shown significant side effects. Regulation of gene expression by AR requires the binding to its natural ligand, dihydrotestosterone (DHT), and assembly of coregulatory proteins (CoR). The blockage of the interaction between DHT-liganded AR and CoR by small molecules ... |
|
| Involvement of Novel Multifunctional Steroid Hormone Receptor Coactivator, E6-Associated Protein, in Prostate Gland Tumorigenesis |
JAN 2008 |
20 pages |
| Authors:
Sathish Srinvasan; MIAMI UNIV FL SCHOOL OF MEDICINE
|
| E3 ubiquitin-protein ligase enzyme, E6-associated protein (E6-AP), is a novel dual function steroid hormone receptor coactivator. E6-AP not only interacts with and enhances the hormonedependent transcriptional activities of various steroid hormone receptors, including androgen receptor (AR), but also is a member of the E3 class of functionally related ubiquitin-protein ligases. Previously, using E6-AP knockout animals we have shown that E6-AP is required for the proper development and growth of prostate ... |
|
| A Novel Mechanism of Androgen Receptor Action |
JAN 2008 |
7 pages |
| Authors:
Jr Roberts Charles T.; OREGON HEALTH AND SCIENCE UNIV PORTLAND
|
| This revised project has as its goal the characterization of a novel alternative product of the Her-2/neu/erbB2 protooncogene derived from intron retention. The product of this splicing mechanism termed herstatin is a secreted protein comprised of the N terminus of the Her-2 receptor tyrosine kinase and a unique intron-encoded C terminus that allows binding to the other members of the EGFR/erbB family. This binding down-regulates erbB expression and inhibits EGF ... |
|
| Selenium is a Chemotherapeutic Agent for the Treatment of Prostate Cancer |
01-Dec-2007 |
20 pages |
| Authors:
Susan J Knox; STANFORD UNIV CA
|
| A large body of data suggests that selenium supplementation may be used as a chemopreventive strategy to reduce the risk of prostate cancer. In spite of this little is known regarding the use of selenium as a cancer therapy. High doses of selenite can deplete cells of the primary intracellular antioxidant glutathione and generate superoxide. The net effect of the metabolism of selenite is a profound alteration in the cellular ... |
|
| Androgen, Estrogen, and the Bone Marrow Microenvironment |
DEC 2007 |
6 pages |
| Authors:
Beatrice Knudsen; FRED HUTCHINSON CANCER RESEARCH CENTER SEATTLE WA
|
| In this project we plan to analyze androgen- and estrogen-responsive gene expression in the bone marrow. We plan to work to: determine if castration-induced gene expression changes in mouse bone marrow are caused by the deficiency of testosterone or estrogen; analyze androgen- and estrogen-sensitive cytokine and gene expression changes in human bone marrow transplanted into NOD/SCID mice and; examine androgen- and estrogen-sensitive gene expression in the bone marrow of patients ... |
|
| Differential Mechanisms of Androgen Resistance |
DEC 2007 |
41 pages |
| Authors:
Orla A. O'Mahony; MICHIGAN UNIV ANN ARBOR
|
| We proposed to study the mechanisms of androgen resistance by focusing on androgen receptor mutations that may arise due to selective pressures of antiandrogen treatment. We have utilized xenograft models and a humanized mouse model (h/mAR xTRAMP) of prostate cancer. Novel AR mutations were found throughout the entire coding region of AR although they did not segregate into distinct regions based on hormonal treatment as was previously reported. Functional analysis ... |
|
| Mitogen-Induced Transactivation of the Androgen Receptor as a Mechanism for Recurrent Prostate Cancer Development |
Dec-2007 |
24 pages |
| Authors:
Liliana A Ponguta; NORTH CAROLINA UNIV AT CHAPEL HILL
|
| The androgen receptor (AR) is required for normal prostate development and the onset and progression of prostate cancer. AR has the modular structure characteristic of steroid hormone receptors, with an NH2-terminal transcriptional activation domain, conserved DNA binding domain, hinge region and carboxyl-terminal ligand binding domain (1, 2). AR mediates the biological effects of androgens by binding testosterone and dihydrotestosterone (DHT) with high affinity (3). Androgen binding in the ligand binding ... |
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| The Role of HOX Proteins in Androgen-Independent Prostate Cancer |
NOV 2007 |
9 pages |
| Authors:
Sunshine Daddario; COLORADO UNIV AURORA CO
|
| HOX genes encode a large family of transcription factors involved in key developmental decisions, and are often aberrantly expressed in cancer. Our laboratory has previously shown that a subset of genes of the HOXC cluster are overexpressed in primary prostate tumors, metastases, and prostate cancer (PCa) cell lines. Increasing transient expression of HOXC8 in LNCaP PCa cells as well as HPr-1 AR non-tumorigenic prostate epithelial cells results in a progressive ... |
|
| Prostate Cell-Specific Regulation of Androgen Receptor Phosphorylation In Vivo |
NOV 2007 |
10 pages |
| Authors:
Samir S. Taneja; NEW YORK UNIV NY SCHOOL OF MEDICINE
|
| We propose that AR phosphorylation at serines 213 and 650 regulate differential target gene expression and recruitment to gene promoters via altered interaction with other cellular transcription factors. To test this hypothesis we have conducted yeast two-hybrid analysis with the N-terminus of wild type AR as well as AR S213A and AR S213E variants. Our preliminary analysis indicates that the screen is preferentially isolating proteins with a known role in ... |
|
| Knockout AR in Prostate |
01-Oct-2007 |
13 pages |
| Authors:
Chawnshang Chang; ROCHESTER UNIV NY
|
| Prostate cancer may progress from an androgen-dependent to an androgen-independent state. The androgen receptor (AR) is expressed throughout this progression. We would like to understand the AR role in this progression. Using lox-Cre methodology, we have generated the mice in which AR function can be abolished in the entire animal (ARKO) or in a tissue specific manner. We will further generate mice that have AR knocked out in prostate only ... |
|
| Androgen Receptor-Mediated Escape Mechanisms From Androgen Ablation Therapy |
OCT 2007 |
10 pages |
| Authors:
Gerhard A. Coetzee; Judd Rice; Li Jia; UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES
|
| Too many prostate-cancer treatments, especially those relying on the suppression of androgen, eventually fail to slow the advance of the disease. One explanation for this situation is the absence of any systematic knowledge on the role and function of the androgen receptor (AR) in the course of prostate cancer development. Recent findings indicate that the AR is the key master regulator (transcription factor) that determines disease progression to androgen independence, ... |
|
| Integrin-Mediated Signaling in Prostate Cancer: Role of KAI1/CD82 in Regulating Integrin and Androgen Receptor Function During Metastasis |
SEP 2007 |
64 pages |
| Authors:
Cynthia K. Miranti; VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI
|
| How prostate tumors become metastatic is virtually unknown. A prostate metastasis suppressor gene, KAI1/CD82, known to associate with laminin receptors, allowed us to test the hypothesis that loss of KAI1/CD82 expression alters the function of laminin integrins in prostate cancer cells, resulting in altered intracellular signaling and increased invasion leading to metastasis. We have demonstrated that in metastatic tumor cells, where elevated c-Met expression and activation by integrins is responsible ... |
|
| Inhibitors for Androgen Receptor Activation Surfaces |
SEP 2007 |
37 pages |
| Authors:
Robert J. Fletterick; SAN FRANCISCO UNIV CA
|
| Studies from this grant led to discovery of a new interaction site on the androgen receptor for binding proteins that regulate the function of the receptor. The protein binders have not been identified, but we showed that the site has the characteristics of functioning in repression. We used X-ray crystallography to discover the binding mode of four compounds that bind to this site. Their binding is accompanied by weakening the ... |
|
| Anti-Androgen Receptor RNA Enzyme as a Novel Therapeutic Agent for Prostate Cancer in Vivo |
AUG 2007 |
18 pages |
| Authors:
Shuo Chen; TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO
|
| Prostate cancer is the second leading cause of cancer death among men in the western world. Androgen plays a crucial role in the development and growth of normal prostate gland and prostate cancer. Action of androgen is mediated by an androgen receptor (AR) and the AR exerts androgen-regulated gene expression. Standard therapy relies on androgen ablation to remove or block the action of androgens. This therapy results in a regression ... |
|
| Arginase: A Novel Proliferative Determinant in Prostate Cancer |
AUG 2007 |
18 pages |
| Authors:
Wayne W. Grody; CALIFORNIA UNIV LOS ANGELES
|
| This project is an investigation of the involvement of the enzyme arginase type II (AII) in the pathogenesis and growth of prostate cancer. Having cloned the AII gene in our laboratory, we unexpectedly discovered that is expressed at high levels in the normal prostate and even higher in neoplastic prostate samples. The purpose of the present research funded by USAMRMC is to examine the expression of AII in a wider ... |
|
| Exercise to Countereact Loss of Bone and Muscle During Androgen Deprivation Therapy in Men with Prostate Cancer |
MAY 2007 |
8 pages |
| Authors:
Wendy M. Kohrt; L. M. Glode; Robert S. Schwartz; Daniel W. Barry; COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO
|
| The original objective was to determine whether a 1-year intensive resistance exercise training (RT) program is more effective than a moderate-intensity walking program in ameliorating the effects on body composition of androgen deprivation therapy (ADT) in men with prostate cancer. It was postulated that: 1) RT will attenuate the declines in bone mineral density (BMD) and fat-free mass (FFM) to a greater extent than walking; and 2) both RT and ... |
|
| A Proteomic Approach to Identify Phosphorylation-Dependent Targets of BRCT Domains |
MAR 2007 |
9 pages |
| Authors:
Zhou Songyang; BAYLOR COLL OF MEDICINE HOUSTON TX
|
| BRCA1 C-terminal (BRCT) domains are novel phosphopeptide binding modules. Cancer-associated missense and deletion mutations have been found in the BRCT repeat regions of BRCA1, suggesting an essential role of BRCT domains in regulating BRCA1activity. In addition, BRCT domains are found in many proteins that regulate DNA damage repair, cell cycle, and genome stability, implying a more global role of BRCT domains in genome stability surveillance. These results suggest that the ... |
|
| A Novel Mechanism of Androgen Receptor Action |
JAN 2007 |
6 pages |
| Authors:
Jr Roberts Charles T.; OREGON HEALTH AND SCIENCE UNIV PORTLAND
|
| This revised project has as its goal the characterization of a novel alternative product of the Her-2/neu/erbB2 proto-oncogene derived from intron retention. The product of this splicing mechanism, termed herstatin, is a secreted protein comprised of the N terminus of the Her-2 receptor tyrosine kinase and a unique, intron-encoded C terminus that allows binding to the other members of the EGFR/erbB family. This binding down-regulates erbB expression and inhibits EGF ... |
|
| Identifying Molecular Factors in Androgen Receptor Nuclear Export |
JAN 2007 |
11 pages |
| Authors:
Yujuan Weng; NORTHWESTERN UNIV EVANSTON IL
|
| Androgen receptor (AR) plays a central role in prostate cancer and the regulation of its nuclearicytoplasmic transport represents another level control of its activity. However how AR is transported into and out of the nucleus remains largely a mystery. Yeast (S. cerevisiae) provides a powerful system to study fundamental cellular mechanisms. Thus we use yeast as a model system to identify factors that are involved in the AR nuclear export. ... |
|
| Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture |
DEC 2006 |
68 pages |
| Authors:
Kristine M. Wiren; Karl Jepsen; OREGON HEALTH AND SCIENCE UNIV PORTLAND
|
| Androgens have been shown to be important mediators of bone growth and remodeling independent of estrogen. We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone. The central hypothesis of this proposal is that AR transactivation in the osteoblast lineage provides key regulatory signals that influence the progression of osteoblast differentiation ... |
|
| The Role of HOX Proteins in Androgen-Independent Prostate Cancer |
NOV 2006 |
7 pages |
| Authors:
Sunshine Daddario; COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO
|
| Our preliminary data demonstrated that HOXC8 and HOXC6 overexpression inhibits androgen receptor (AR)-mediated signaling in human prostate cancer (PCa) cells. Based on these findings, coupled together with previous reports demonstrating that homeodomain-containing proteins interact with and inhibit the histone-acetyltransferase (HAT) activity of the steroid receptor coactivators CBP and p3001, we hypothesized that HOXC8 inhibits AR-mediated signaling through inhibition of CBP/p300 HAT activity. In support of this hypothesis, we have recently ... |
|
| A New Concept for Androgen Receptor-Independent Growth of Prostate Cancer |
NOV 2006 |
15 pages |
| Authors:
Guo-fu Hu; Hiroko Kishikawa; Norie Yoshioka; HARVARD MEDICAL SCHOOL BOSTON MA
|
| Angiogenin is an angiogenic ribonuclease that is upregulated in prostate cancer. The objective of this project is to explore the role angiogenin plays in the development of androgen-independent disease. The hypothesis to be tested is that angiogenin plays an essential role in rRNA transcription in prostate cancer cells and that constitutive nuclear translocation of angiogenin is a driving force for transition to androgen independence. Toward this goal, we have carried ... |
|
| The Role of Siah1-Induced Degradation of Beta-Catenin in Androgen Receptor Signaling |
NOV 2006 |
21 pages |
| Authors:
Shu-ichi Matsuzawa; BURNHAM INST LA JOLLA CA
|
| The androgen receptor (AR) signaling-pathway plays crucial roles in the growth and progression of prostate cancer cells. Recent studies indicate that beta-Catenin physically binds to AR and enhances its transcriptional activity in a ligand dependent manner. p53 has also been implicated in AR signaling because of its ability to induce expression of Siah1, which hinds and activates E3 ligase complexes which degrade beta-Catenin. In this study, we demonstrated the biological ... |
|
| Prostate Cell Specific Regulation of Androgen Receptor Phosphorylation In Vivo |
NOV 2006 |
7 pages |
| Authors:
Samir Taneja; Susan Logan; Brian Dynlacht; Michael Garabedian; Derick Mitchell; NEW YORK UNIV SCHOOL OF MEDICINE NY
|
| On the basis of previous studies in which we analyze AR phosphorylation in vivo we propose that AR phosphorylation at serines 213 and 650 regulate differential target gene expression and recruitment to gene promoters via altered interaction with other cellular transcription factors. To test this hypothesis we have conducted yeast two-hybrid analysis with the N-terminus of wild type AR as well as AR S213A and AR S213E variants. Our preliminary ... |
|
| Androgen Receptor-Mediated Escape Mechanisms from Androgen Ablation Therapy |
OCT 2006 |
18 pages |
| Authors:
Gerhard A. Coetzee; Judd Rice; Li Jia; UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES
|
| Too many prostate-cancer treatments, especially those relying on the suppression of androgen, eventually fail to slow the advance of the disease. One explanation for this situation is the absence of any systematic knowledge on the role and function of the androgen receptor (AR) in the course of prostate cancer development. Recent findings indicate that the AR is the key master regulator (transcription factor) that determines disease progression to androgen independence, ... |
|
| Selective Androgen Receptor Downregulators (SARDs): A New Prostate Cancer Therapy |
OCT 2006 |
27 pages |
| Authors:
Rumi S. Bhattacharyya; LELAND STANFORD JUNIOR UNIV STANFORD CA
|
| The androgen receptor (AR) plays a key role in the development and progression of prostate cancer. Targeting the AR for down-regulation would be a useful strategy for treating prostate cancer especially hormone-refractory or androgen independent prostate cancer (AIPO). In the present study we showed that the antiestrogen Fulvestrant (ICI 182,780, ICI) effectively suppressed AR expression in several human prostate cancer cells including androgen-independent cells. In LNCaP cells 101(10 microM) treatment ... |
|
| Regulation of AR and (beta)-Catenin Signaling by Pin 1 in Prostate Cancer |
OCT 2006 |
20 pages |
| Authors:
Shaoyong Chen; BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
|
| One part of the Final report was included in the attached Manuscript, demonstrating a positive role of Pin1 in PCa progression. The mechanisms include that Pin1 can enhance beta-catenin nuclear localization, TCF/beta-catenin dependent Topflash activity, and c-Myc and Cyclin D1 expression, and disrupt AR-mediated suppression of TCF/beta-catenin signaling. We provided additional data suggesting Pin1 reduces AR transcriptional activity and PSA expression, mediated by repression of the N-C interaction. We also ... |
|
| AR-NcoR Interaction as a Therapeutic Target for Prostate Cancer Prevention and Treatment |
OCT 2006 |
8 pages |
| Authors:
Steven P. Balk; BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
|
| Aim 1 is to determine the precise molecular basis for NCoR binding to the RU486 liganded AR. Since the previous report we have used chromatin immunoprecipitation to demonstrate that RU486 enahnces AR NCoR recruitment to AR assembled on androgen regulated genes. We have also generated the additional AR and NCoR mutants to define the precise amino acids mediating the interaction. Aim 2 is to determine whether NCoR recruitment can suppress ... |
|
| The Role of (BETA)-Catenin in Androgen Receptor Signaling |
OCT 2006 |
10 pages |
| Authors:
Neil A. Bhowmick; VANDERBILT UNIV NASHVILLE TN
|
| Previously that the ceil adhesion molecule u-catenin forms a complex with the androgen receptor (AR) and modulate itstranscription. The cross talk between u-catenin and AR signaling can play an important role in AR transcriptional in prostatecancer progression. Our preliminary data seem indicate stromally derived paracrine Wnt family members activate theepithelial frizzled receptor to enable prostate epithelial survival in an androgen deficient environment. We will continue totest the original hypothesis that ... |
|
| Inhibitors for Androgen Receptor Activation Surfaces |
SEP 2006 |
45 pages |
| Authors:
Robert J. Fletterick; CALIFORNIA UNIV SAN FRANCISCO
|
| The androgen receptor (AR) is a proven therapeutic target for treating prostate cancer. Known therapeutics target the ligand binding domain (LBD) at the exact place where dihydrotestosterone (DHT) binds. Upon binding DHT, AR reorganizes to form new interaction surfaces such as the AF2 surface that attracts coregulators. AF2 has been proposed as a second therapeutic target as coactivator recruitment is a key step for AR function. We developed two screening ... |
|
| Effects of Androgen Ablation on Anti-Tumor Immunity |
SEP 2006 |
46 pages |
| Authors:
W. M. Kast; UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES
|
| Androgen Ablation (AA) constitutes the most common therapy for the treatment of advanced prostate cancer. While initially effective at reducing tumor burden, most patients recur with androgen insensitive disease. AA affects the immune system both systemically as well as at the prostate. Androgens have immunosuppressive effects and it is therefore of interest to investigate if immunotherapy can benefit from androgen ablation when immunosuppression is reduced. AA results in infiltration of ... |
|
| Evaluation of Roles of Interferon Gamma Regulated Genes in Inhibition of Androgen-Independent Prostate Cancer |
AUG 2006 |
87 pages |
| Authors:
Eva Corey; WASHINGTON UNIV SEATTLE
|
| CaP presents its greatest challenge to clinicians when it progresses to the hormone-independent state. Therapeutic methods which are effective regardless of androgen response, or even target androgen-independent CaP specifically, are of special medical and scientific interest. We have shown that estradiol (E2) can inhibit growth of hormone independent CaP in vivo. Among the genes up-regulated by E2 are IFN-regulated genes. The LuCaP 35V xenograft does not grow in vitro; for ... |
|
| Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer |
AUG 2006 |
29 pages |
| Authors:
James P. Grigsby; Angela G. Brega; COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO
|
| The purpose of this project was to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment (ADT). The cognitive abilities of androgen deprivation patients were compared with those of a sample of healthy men. We undertook collection of data from 40 men on intermittent or continuous ADT and an age- and education-matched sample of 34 control subjects. Our major ... |
|
| Evaluation of Feasibility for a Case-Control Study of Adrenal Androgen Production in Postmenopausal Women With Breast Cancer |
JUL 2006 |
17 pages |
| Authors:
Joanne F. Dorgan; FOX CHASE CANCER CENTER PHILADELPHIA PA
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| Postmenopausal women with elevated serum estrogens and androgens are at an increased risk of breast cancer [I]. Dehydroepiandrosterone sulfate (DHEAS) is secreted only by the adrenals, and elevated serum DHEAS levels in postmenopausal women who develop breast cancer suggest increased adrenal androgen production. The objective of this pilot study was to evaluate variation in responsiveness of adrenal hormones to ACTH stimulation in healthy postmenopausal women. We also evaluated variation in ... |
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