bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1703: Osteoblastic differentiation induced by PSA: Role of Wif-1 and TGF-β
Authors: Nadiminty Nagalakshmi , Chun Jae Yeon , Lou Wei , Gao Allen C. 
Published: February 2011

Abstract
Introduction: The high prevalence of osteoblastic bone metastases in prostate cancer likely involves the production of osteoblast-stimulating factors by prostate cancer cells. The identity of the factors responsible for the homing of circulating prostate cancer cells to the bone remains unknown. Prostate specific antigen (PSA) is a serine protease produced by prostate cancer cells and is an important serological marker for prostate cancer. Our previous studies suggested that PSA may be involved in the induction of osteoblastic differentiation. In this study, we examined the involvement of Wnt inhibitory factor 1 (Wif-1) and Transforming growth factor β (TGF-β) in osteoblastic differentiation induced by PSA in SaOS-2 human osteosarcoma cells.
Methods: Microarray analysis of RNAs from Saos-2 cells stably expressing PSA and vector controls was performed and the results were validated by northern blotting. The potential role of Wif-1 and TGF-β in osteoblatic differentiation induced by PSA was examined by alkaline phosphatase assays, luciferase assays and northern analysis.
Results: PSA was found to induce bone remodeling in SaOS-2 cells as evidenced by increases in alkaline phosphatase activity, mineral deposition and osteogenic gene expression. Saos-2 cells expressing PSA exhibited markedly upregulated expression of markers of osteoblastic differentiation like collagen type 1, osteocalcin, Runx-2, alkaline phosphatase and bone sialoprotein compared to parental Saos-2 cells and vector controls. Treatment of SaOS cells with exogenous enzymatically active PSA produced similar results, suggesting that osteoblastic differentiation may be regulated by PSA. Among the genes found to be regulated by PSA expression, TGF-β and Wif-1 were examined further. PSA enhanced the expression and activation of TGF-β as shown by higher levels of TGF-β-responsive reporter activity and increase in expression of TGF-β receptors I and II. Overexpression of Wif-1 in SaOS-2 cells enhanced osteogenic gene expression, while inhibition of Wif-1 expression in PSA-expressing cells resulted in reduction of alkaline phosphatase activity, a marker of osteoblastic differentiation.
Conclusions: PSA-induced bone remodeling was mediated by enhanced expression of several markers of osteoblastic differentiation and modulation of TGF-β and the Wnt/β-catenin pathways. These results suggest that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of development of osteoblastic metastases. These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1703.
Abstract 1710: Epigenetic repression of regulator of G-protein signaling 2 promotes prostate cancer progression
Authors: Tu Yaping , Wolff Dennis W. , Gatalica Zoran , Xie Yan , Abel Peter W. 
Published: February 2011

Abstract
Prostate cancer is the most common cancer in American men and acquisition of androgen independence by prostate cancer is the key problem causing prostate cancer progression to highly aggressive form of cancer, leaving limited modalities in its treatment. Recent studies suggest that G protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to development of androgen independence. We previously reported that RGS2, an inhibitor of GPCR signaling, inhibits androgen-independent AR activation in prostate cancer cells (Cao et al., (2006) Oncogene, 25: 3719-3734). Here, we report that RGS2 protein expression was significantly reduced in human prostate cancer specimens compared to adjacent normal prostate tissues. Interestingly, RGS2 repression in androgen-independent prostate cancer cells and human prostate cancer specimens is not simply due to the loss of the RGS2 gene. Instead, methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the RGS2 gene promoter correlates with RGS2 down-regulation in prostate cancer cells and human prostate cancer specimens. Hypermethylation of the RGS2 gene promoter abolished its promoter activity and suppressed RGS2 gene expression. Conversely, the DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine induced re-expression of RGS2 in androgen-independent prostate cancer cells via demethylation of the RGS2 promoter to inhibit androgen-independent prostate cancer growth. Furthermore, ectopic re-expression of RGS2 in androgen-independent prostate cancer cells by RGS2-adenovirus infection suppressed tumorigenicity and growth of xenografts in castrated nude mice. Taken together, our results suggest that RGS2 repression due to hypermethylation of its promoter could unmask a latent pathway for AR activation by various GPCRs, thus contributing to prostate cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1710.
Abstract 1712: Androgen receptor splicing variants promote therapeutic resistance in prostate cancer
Authors: Guo Zhiyong , Yang Xi , Sun Feng , Linn Douglas E. , Jiang Richeng , Chen Hege , Chen Hegang , Kong Xiangtian , Melamed Jonathan , Tepper Clifford G. , Kung Hsing-Jien , Brodie Angela M. H. , Edwards Joanne , Qiu Yun 
Published: February 2011

Abstract
Androgen receptor (AR) plays a key role in progression to incurable castration-resistant prostate cancer. Recently, we and others have identified multiple alternatively spliced AR isoforms in hormone refractory prostate cancer cells. These AR splice variants contain the intact N-terminal transactivation domain and the DNA binding domain, but lack the ligand binding domain. They function as constitutively active transcription factors and their activity is independent of androgen or anti-androgens. Our tissue microarrays analysis on 429 human prostate tissue samples revealed that AR3, one of the major AR splice variants, is significantly up-regulated during prostate cancer progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers castration-resistant growth of prostate cancer cells, whereas specific knockdown of AR3 expression in hormone-resistant prostate cancer cells attenuates their growth under androgen-depleted conditions, suggesting an indispensable role of AR3 in castration-resistant growth of prostate cancer cells. Furthermore, our gene expression microarray analysis showed that AR3 regulates a unique set of target genes which are not regulated by the prototype AR, suggesting that AR3, as an independent transcription factor, utilizes a distinct transcription programs to achieve its distinct and specific biological functions which are important for castration-resistant growth.
In addition to its role in the androgen-ablation resistance, the AR isoforms may also be involved in chemotherapeutic resistance. We found that AR3 is overexpressed in chemotherapeutic resistant prostate cancer cell lines that are more tumorigenic, compared with their parental drug-sensitive lines. Therefore, aberrant expression of AR splicing variants may be a general mechanism underlying the development of multiple therapeutic resistances in prostate cancer.
Taken together, our data suggest that AR3 may potentially serve as a prognostic marker to predict patient outcome in response to hormonal and chemo therapy, and targeting these AR splicing variants may offer more effective treatment for advanced prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1712.
Abstract 1713: Activation of the aryl hydrocarbon receptor and down-regulation of the androgen receptor in prostate cancer cells by the curcumin analog C48
Authors: Fajardo Alexandra M. , Bowles Harmony J. , MacKenzie Debra A. , Vander Jagt David L. , Bisoffi Marco , Thompson Todd A. 
Published: February 2011

Abstract
The androgen receptor (AR) is a critical player in prostate cancer (CaP) development and progression and is a well-established therapeutic target. Recent studies have shown the aryl hydrocarbon receptor (AhR) is an important modulator of the AR acting as an adaptor for ubiquitin ligases and increasing the degradation of the AR. The natural product curcumin, a known inhibitor of the AR, has been shown to modulate the activity of the AhR. We have identified a curcumin analog, C48, which potently inhibits CaP cell proliferation. The purpose of this study was to identify molecular pathways that contribute to the effects of C48 on CaP cells, which may involve AR down-regulation through an AhR-mediated mechanism. Androgen-sensitive LAPC4, LNCaP and C4-2 CaP cells were used to perform these studies. We have found that C48 potently reduces AR expression levels in CaP cells in a dose- and time-dependent manner. C48 also decreased expression of genes induced by the AR, such as prostate specific antigen. We have found that a potent AhR activator, benzo(a)pyrene, down-regulates AR protein expression in CaP cells. As with benzo(a)pyrene, C48 was found to activate the AhR as determined using an AhR-activated reporter system. In addition, C48 potently induced markers of AhR activation including cytochrome P450 1A1 and aldoketoreductase 1C1 in CaP cells. Previous studies (e.g., Fritz et al., 2007) have shown that the AhR may act as a prostate cancer suppressor. Results from this study may facilitate the identification of safe and effective agents, such as the curcumin analog C48, that target AR down-regulation as a potential therapeutic strategy for prostate cancer without the toxicities associated with agents such as benzo(a)pyrene.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1713.
Abstract 1714: Transcriptional networks downstream of the AR identify clinically relevant prostate cancer targets
Authors: Massie Charlie , Lynch Andy , Stark Rory , Ramos-Montoya Anthony , Fazli Ladan , Warren Anne , Scott Helen , Bon Helene , Sharma Naomi , Zecchini Vinny , Matthews Nik , Osborne Michelle , Hadfield James , Swatton Jane , McArthur Stewart , Adryan Boris , Grigorenko Elena , Watt Carolyn , McEwan Iain , Rennie Paul , Neal David , Mills Ian G. 
Published: February 2011

Abstract
The AR signalling axis is central to Prostate Cancer (PrCa) biology, shown by its use in both screening (PSA) and treatment of the disease (androgen deprivation therapy). Identifying direct target genes of the AR will provide a better understanding the key signalling pathways controlled by the AR in PrCa and could lead to improved biomarkers and future therapeutic targets for the disease. To this end we have performed fine mapping of androgen responsive gene expression in prostate cancer cell lines using Illumina bead-arrays, coupled with AR chromatin-immunoprecipitation and Solexa sequencing technology (ChIP-seq). This approach generated over ten thousand candidate AR target genes. We have then undertaken large scale, cross-platform validation using BioTrove Realtime PCR panels which allow the measurement of &gt;600 transcripts simultaneously. Using this combination of approaches we have identified and validated several hundred AR regulated genes. We found that metabolic enzymes and kinases were significantly enriched in the set of direct AR regulated genes. In nine independent clinical gene expression studies we found that the most consistently up-regulated AR target gene was a calcium regulated kinase. At the protein level this kinase showed increased expression in two independent patient cohorts. A small molecule inhibitor of this kinase reduced the growth of a panel of PrCa cell lines in vitro and tumour growth in xenograft models. Interestingly, we found that the levels of this AR regulated kinase were reduced in clinical PrCa following androgen deprivation therapy, but were raised in Castrate Resistant disease. Therefore, we have identified an AR regulate kinase which contributes to tumour growth and is a potential marker and therapeutic target in both hormone naïve and anti-androgen resistant disease. In summary, these data show that combining expression analysis, ChIP-seq and high through-put validation has identified a framework to understand the oncogenic functions of the AR in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1714.
Abstract 1718: ErbB-2 acts as coactivator of Stat3 in heregulin-induced breast cancer growth
Authors: Béguelin Wendy , Flaqué María C. Díaz , Proietti Cecilia J. , Rivas Martín A. , Tkach Mercedes , Charreau Eduardo H. , Schillaci Roxana , Elizalde Patricia V. 
Published: February 2011

Abstract
We have previously demonstrated that heregulin (HRG), a ligand for ErbB receptors, activates signal transducer and activator of transcription 3 (Stat3) in primary cultures of ErbB-2 overexpressing C4HD cells, from a murine progestin-dependent mammary tumor. ErbB-2 activity is an absolute requirement in the mechanisms of HRG stimulation of Stat3 activity. Recent findings have demonstrated ErbB-2 nuclear migration and its function as a transcription factor. In this work, we studied whether HRG induces ErbB-2 nuclear migration and its interaction with Stat3 in breast cancer cells. We demonstrated that HRG induces ErbB-2 nuclear migration and colocalization with Stat3 in C4HD and human T47D breast cancer cells. Cyclin D1 is a cancer-related gene that contains Stat3 binding sites (GAS sites) but lacks ErbB-2 response elements (HAS sites). By chromatin immunoprecipitation assays (ChIP) and sequential ChIP, we demonstrated that HRG induces in vivo binding of Stat3 and ErbB-2 to the GAS sites of the cyclin D1 promoter. This finding prompted us to evaluate the ability of HRG to regulate cyclin D1 expression. By inhibiting ErbB-2 and Stat3 activation or silencing their expression, we demonstrated that ErbB-2 and Stat3 participate in the mechanism of HRG-induced cyclin D1 protein expression. Next, we explored whether HRG induces cyclin D1 promoter directly via Stat3 binding to its response elements. C4HD and T47D cells transiently transfected with a cyclin D1 promoter luciferase construct showed an enhanced transcriptional activity with HRG treatment. Overexpression of increasing amounts of ErbB-2 wt resulted in a dose-dependent ErbB-2 capacity to enhance Stat3 transcriptional activity induced by HRG. On the other hand, transfection with increasing amounts of an ErbB-2 mutant that is defective in nuclear entry but retains its cell-surface location and functions (ErbB-2ΔNLS) resulted in abrogation of HRG-induced Stat3 activation of cyclin D1 promoter. Finally, we addressed the effect of targeting ErbB-2 in in vivo HRG-dependent growth of C4HD breast tumors. Transfection of C4HD cells with the ErbB-2ΔNLS expression vector significantly inhibited these cells’ ability to form tumors in syngeneic mice. Taken together, these results suggest a new role of ErbB-2 as a coactivator in the mechanism of HRG-induced transcriptional activation of Stat3. We also found nuclear ErbB-2 to be a requisite for HRG stimulation of in vitro and in vivo breast cancer growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1718.
Abstract 1719: Leptin, an obesity-related adipocytokine, promotes accelerated growth of Wnt-1 mammary tumors and modulates basal-like and luminal tumor markers
Authors: Zheng Qiao , Smith Sarah , Zhu Jinling , Hursting Stephen D , Reizes Ofer 
Published: February 2011

Abstract
Over 2/3 of the US population is obese or overweight, a condition associated with increased risk and decreased survival of various cancers including breast cancer. There is a large unmet medical need to identify mechanisms underlying the link between obesity and cancer. The purpose of these studies is to elucidate the obesity-dependent mechanisms promoting aggressive mammary tumor growth. Circulating levels of leptin, an adipocyte-secreted cytokine that regulates body weight, are elevated in obese and overweight individuals. We orthotopically transplanted tumor cells derived from primary spontaneous MMTV-Wnt-1 tumors into morbidly obese leptin-deficient (ob/ob; lack wild-type leptin) and leptin receptor-deficient (db/db; hyperleptinemic) mice. The MMTV-Wnt-1 tumors, like many human breast tumors, are mixed lineage giving rise to tumors expressing both basal and luminal tumor markers. We determined that orthotopic transplant of MMTV-Wnt-1 tumor cells into obese db/db mice, with high serum leptin, leads to accelerated tumor growth. In contrast, transplant into obese ob/ob mice leads to small, disorganized tumors. More importantly, tumors from leptin-deficient ob/ob mice are predominantly comprised of differentiated epithelial (E-cadherin) and myoepithelial (α—SMA and keratin 14) tumors cells and surprisingly lack basal (keratin 5 and 6) and luminal (keratin 8) lineage tumor cells. Indeed, we determined that AKT cell survival/proliferation pathway was suppressed in the tumors from leptin-deficient mice. The phospho-AKT (p-AKT) immunopositive cells were primarily also expressing keratin 6, and not αSMA or keratin 8, indicating that AKT is activated in the keratin 6 basal-like tumor cells. These studies are highly significant because they indicate leptin, elevated in obese patients, promotes aggressive tumor growth by targeting survival, proliferation, and/or differentiation of subpopulations of mammary tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1719.
Abstract 1721: A steroid-based drug that binds estrogen receptor beta can inhibit cancer cell proliferation by blocking chromosome replication
Authors: Weitman Steven D. , Bittner Michael , Hershberger Pamela , Babine Robert E. , Nye Steven , Yarger James 
Published: February 2011

Abstract
Our approach for developing a cancer therapeutic is based on the notion that the estrogen receptors alpha (ER-alpha) and beta (ER-beta) function in opposing manners towards events involved in controlling cell growth and proliferation. If the proposed inhibitory function of ER-beta is accurate, we predict that treatment of cancer cells with an ER-beta agonist may lead to cessation of cell division and potentially to cell death. Towards that end, we have discovered a family of first-in-class compounds for treating cancer that function by blocking chromosome replication in rapidly dividing cells. NDC-1022 and NDC-1308 are estradiol analogs which vary only in the length of the 6-alkoxyalkyl group at the carbon 6 position. Importantly, the length of the 6-alkoxyalkyl group may impact the function of the compounds since in silico modeling studies predict a difference in how the side-chains of NDC-1022 and NDC-1308 are bound within the ligand binding sites of ER-alpha and ER-beta. To understand the mechanism of action for these compounds, competitive binding studies were carried out with either recombinant human ER-alpha or ER-beta in the presence of labeled estradiol. The results show that the NDC compounds preferentially bind to the ER-beta receptor compared to the ER-alpha receptor. To determine how the NDC compounds affect cell growth, 201T NSCLC cells were incubated with 100 µm of NDC-1022. After 48 hours, NDC-1022 caused a reversible cell cycle arrest at G0/G1 for the majority of cells. The level of cytotoxicity was determined by treating 14 different human tumor cell lines with a serial dilution of the NDC compounds. The EC50 data suggests that NDC-1308 (10-20 uM) is about 3 to 8.5-fold more potent than NDC-1022 (30-85 uM). We propose that this difference in potency is due to NDC-1308 making additional non-polar interactions within the receptor ligand binding sites compared to NDC-1022. Finally, gene expression studies were carried out using microarray to identify the mechanism of action for cytotoxicity. Three human tumor cell lines (A549-lung, SKOV-3-ovary, and Panc-1- pancreatic) were treated with the NDC compounds for 24 hours. Both NDC-1022 and NDC-1308 exhibit a substantial reduction in the transcription of 27 genes critical for chromosome replication, a cellular process exaggerated in most cancer cells and therefore a relevant therapeutic target. We conclude that NDC-1022 and NDC-1308 impact all rapidly growing cells without regard to any underlying mutation and therefore could be used to treat a wide range of cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1721.
Abstract 1725: Neuroendocrine modulation of anoikis
Authors: Armaiz-Pena Guillermo N. , Halder Jyotsnabaran , Nick Alpa M. , Stone Rebecca L. , Spannuth Whitney A. , Deavers Michael T. , Allen Julie K. , Han Liz Y. , Kamat Aparna A. , Shahzad Mian M.K. , McIntyre Bradley W. , Diaz-Montero Claudia M. , Jennings Nicholas B. , Lin Yvonne G. , Merritt William M. , DeGeest Koen , Mejias Pablo E. Vivas , Berestein Gabriel Lopez , Schaller Michael D. , Cole Steven W. , Lutgendorf Susan K. , Sood Anil K. 
Published: February 2011

Abstract
Chronic stress and associated hormones are known to affect multiple systems including immunological and endocrinological functions, but the effects on cancer growth and progression are not fully understood. Here, we demonstrate that chronic stress and associated increases in catecholamines, protect tumor cells from anoikis and promote growth by activating focal adhesion kinase (FAK). These effects involve phosphorylation of FAKY397 associated with actin-dependent Src interaction with membrane-associated FAK. In human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAKY397, which was in turn linked to substantially accelerated mortality. These data suggest that FAK modulation by stress hormones, especially norepinephrine and epinephrine, can contribute to tumor progression in ovarian cancer patients. These findings further point at potential new therapeutic targets for cancer management.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1725.