bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2102: The germline nonsense variant K1019X results in loss of tumor suppressing function of EphB2 in prostate cancer cells
Authors: Salhia Bodour , Hussain Khateeb Hyder , Carpten John 
Published: July 2012

Abstract
Prostate cancer (PC) is the most common form of cancer in all men and also the second leading cause of cancer related deaths. On average, African American (AA) males are twice as likely to develop prostate cancer and three times more likely to die from it compared with Caucasian men. Previously we combined nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization for the genome-wide identification of genes with biallelic inactivation involving nonsense mutations and loss of the wild-type allele (Huusko et al, Nature Genetics 2004). This approach enabled us to identify previously unknown mutations in the receptor tyrosine kinase gene EphB2 in ∼7% of prostate tumors. EPHB2 is a member of the tyrosine kinase receptor family of proteins and regulates intracellular signaling pathways involved in cell growth, migration, adhesion, and polarity. Furthermore, there is also strong evidence for EphB2 as a tumor suppressor in colorectal cancer. There are two main isoforms (1 and 2) of the EphB2 gene, which is the result of alternative splicing. Previous studies from our lab also shows that a germline 3055A&gt;T nonsense variant (K1019X) in the EphB2 gene differs in frequency between AA and Caucasian males, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA. The DU145 prostate cancer cell line, originating from a brain metastasis, carries a truncating mutation of isoform 1 of EphB2 and a deletion of the remaining allele. Transfection of DU145 cells, which lack functional EPHB2, with wild-type EPHB2 suppresses clonogenic growth. The goal of this project is to determine the effect of the K1019X mutation on the growth of DU145 cells. Introduction of wild-type and 3055A&gt;T EphB2 into DU145 cells using a lentiviral-based vector led to successful expression as seen by RT-PCR and western blot analysis. We also demonstrated using RT-PCR and western blot analysis that while DU145 cells lack functional expression of the isoform 1, there is expression of the second isoform, implying that the tumor suppressing function of EPHB2 may be unique to isoform 1. Using a sulforhodamine B assay we demonstrated that the K1019X mutation inhibits growth suppression of DU145 cells as compared with wild-type EPHB2. These initial findings suggest that the K1019X is a true functional variant and support the role of the K1019X in increasing prostate cancer risk in AA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2102. doi:10.1158/1538-7445.AM2011-2102
Abstract 2107: Downregulation of ASPP2 in choriocarcinoma contributes to increased migratory potential through Src activation
Authors: Mak Victor CY , Lee Lee , Siu Michelle KY , Wong Oscar GW , Lu Xin , Ngan Hextan YS , Wong Esther , Cheung Annie NY 
Published: July 2012

Abstract
Gestational choriocarcinoma is a malignant tumour derived from placental trophoblast and is the most aggressive member of gestational trophoblastic disease (GTD). Apoptotic stimulating protein of p53-2 (ASPP2) is a tumor suppressor member of the ASPP family which transactivates p53-dependent apoptotic pathway. In this study, we examined the expression profile of ASPP2 in choriocarcinoma in comparison with normal placentas and hydatidiform moles which is a type of GTD that carries malignant potential. Results from quantitative PCR and immunohistochemical studies showed that downregulation of ASPP2 was detected in choriocarcinoma at both RNA and protein levels. ASPP2-transfected choriocarcinoma cells (namely JEG-3 and JAR) showed an increase in apoptosis and a decrease in cell migration as detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and wound healing assays respectively, illustrating the complex action of ASPP2 on cell functions other than program cell death. Transfection of ASPP2 but not ASPP1, another tumor suppressive member of the ASPP family, decreased Src-pY416 phosphorylation, suggesting an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-induced inactivation of Src could be abolished by RNA interference using Csk small interfering RNA (siRNA). All these findings suggested that the ability of ASPP2 to attenuate Src activation was specific to ASPP2 in a Csk dependent manner. Taken together, we demonstrated a loss of tumor suppressive ASPP2 in choriocarcinoma with effects on cell migration as well as apoptosis. We also unveiled a possible mechanistic link between ASPP2 and Csk/Src signaling pathway, implicating the multiple cellular functions of ASPP2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2011-2107
Abstract 2120: Secreted protein acidic and rich in cysteine, like 1(SPARCL1), inhibits aggressiveness and relates to better prognosis in colorectal cancers
Authors: Zhang Hang , Hu Hanguang , Ge Weiting , Liu Xiyong , Chen Huarong , Yu Shujing , Zhang Suzhan , Yen Yun , Zheng Shu 
Published: July 2012

Abstract
Secreted protein that's acidic and rich in cysteine, like 1(SPARCL1), an extracellular de-adhesion glycoprotein, was down-regulated in several solid cancers such as non-small cell lung cancer and pancreatic cancer. Our previous study revealed that expression of SPARCL1 was negatively related to liver metastasis of colorectal cancer (CRC). To clarify the function of SPARCL1 and its mechanism in CRC, the overexpression cell clone, RKO-SPARCL1, was created for illustrating biological behavior of SPARCL1 in vitro and in vivo. It was shown that SPARCL1 significantly reduced colony formation (p=0.027), invasion ability (p=0.001) and adhesion (p=0.04) of CRC cells in vitro. In comparison with vector control (RKO-pLXSN), RKO-SPARCL1 displayed significantly reduction in liver metastatic nodules in intrasplenic injection nude mice model (p=0.009). Meanwhile, tissue samples from 412 CRC patients were reassembled as tissue microarray for an outcome study. The antibody against SPARCL1 was developed for Immunohistochemistry (IHC) staining to assess the expression level of SPARCL1. Uni- and multivariate Logistic analysis demonstrated that SPARCL1 was negatively related with poorly tumor differentiation (p=0.001), lymph node metastasis (Odds ratio, OR=0.67, 95% 0.45-1.00) and distant metastasis (OR=0.39, 95% 0.18-0.82). The Kaplan-Meier analysis revealed that overexpression of SPARCL1 was significantly related to better overall survival in CRCs (p=0.004). Furthermore, the multivariate COX proportional hazard analysis demonstrated that SPARCL1 significantly reduced the risk of death from CRC (Hazard ratio, HR=0.57, 95% 0.39-0.84). Based on bioinformatics gene ontology analysis for gene expression microarray, overexpression of SPARCL1 significantly inhibited focal adhesion pathway and other tumor-associated oncogenes, such as S100A4 and ERBB3, in RKO cell line. Therefore, it is concluded that SPARCL1 may function as a tumor suppressor inhibiting the aggressiveness of cancer cells and reducing the risk of death from CRCs. It is suggested that SPARCL1 may serve as a prognostic biomarker for CRCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2011-2120
Abstract 2124: Comprehensive analysis of hormone receptor status during prostate cancer progression: A novel prognostic role for pAR and ERbeta
Authors: Ruiz Christian , Zlobec Inti , Stuerm Susanna , Rey Silvia , Schneider Sandra , Oeggerli Martin , Gasser Thomas , Zellweger Tobias , Bachmann Alexander , Bubendorf Lukas 
Published: July 2012

Abstract
Aims: Patients with advanced prostate cancer (PrCa) are usually treated with androgen withdrawal. Although this therapy is effective at the beginning, nearly all prostate cancers become refractory to it. Hormone receptors play a crucial role during this progression. Aim of this study was to analyze the genomic and expression status of hormone receptors in prostate cancer and the evolution of these markers in the development of castration-resistance.
Methods: We selected 915 transurethral resection (TURP) specimens from 107 untreated PrCa and from 101 castration-resistant (CR) PrCa. These samples were used for the construction of a tissue microarray (TMA). In addition, we included 56 distant metastases. We analyzed the androgen receptor (AR) gene copy number by fluorescence in-situ hybridization and the expression profiles of AR, phosphorylated AR (pAR), ERβ, ERα and the proliferation marker Ki67 by immunohistochemistry.
Results: AR gene amplification was almost restricted to PrCa and was significantly associated with increased AR protein expression (p&lt;0.0001) and higher tumor cell proliferation (p=0.001). Interestingly, although pAR was predominantly found in the CR PrCa (p=0.003), pAR expression in untreated PrCa patients identified a subgroup of patients with poor survival (p&lt;0.05). In contrast to ERα expression, which was restricted to CR PrCA cells (10%), ERβ was found in 40% of the PrCa, independent of treatment status. Similar to pAR, the presence of ERβ in untreated patients was significantly associated with adverse prognosis (p&lt;0.005).
Conclusions: This is the first comprehensive study comparing the hormonal receptor status in a large cohort of hormone-naïve and CR PrCa. Our results strongly suggest a major role for pAR and ERβ in untreated PrCa. Expression of these markers might be a mechanism of CR tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2124. doi:10.1158/1538-7445.AM2011-2124
Abstract 2125: Circadian crosstalk modulation of estrogen receptor alpha promoter activity
Authors: Villa Linda M. , Cousins Sarah , Capelluto Daniel G.S. , Finkielstein Carla V. 
Published: July 2012

Abstract
The proper timing of cell division is a major factor contributing to the regulation of normal growth and emerges as a fundamental process in the development of most cancers. The existence in most, if not all, living organisms of many behavioral and physiological events that occur at well-defined and controlled times argues for the presence of time-keeping systems that allow them to adapt to cyclic changes in environmental conditions. Disruption of circadian rhythm has recently emerged as a new potential risk factor in the development of cancer, pointing to the core gene period 2 (per2) as a tumor suppressor. Circadian disruption has been epidemiologically linked to a raising number of estrogen dependent tumors identified in night-shift workers. In the present study, we investigate the signaling molecules that modulate the circadian expression of estrogen receptor alpha (ERa). ERa mRNA oscillates in a 24 h period and, unlike the circadian factor Per2, ERa peaks during the light phase of the day. Because up regulation of ER relates to tumor development, defining the mechanisms of ERa expression will contribute to our comprehension of cellular proliferation and regulation of normal developmental processes. Transcriptional activation of ERa was measured using a reporter system in Chinese Hamster Ovary and MCF-7 cell lines. Data show that Per2 influence ERa transcription through a non-canonical mechanism independent of its circadian counterparts. Promoter analysis using the Alibaba 2.0 suite revealed the presence of various putative novel partners. Among them, OCT-1 was found to directly interact with Per2 and with corresponding response element within the ERa promoter bit in vitro and endogenously in CHO and MCF-7 cells. The predicted binding site of OCT-1 is 867 bps downstream of the promoter. Pull-down assays were used to map direct interaction of various Per2 recombinant proteins and the DNA-binding domain of OCT-1. Radiolabeled OCT-1 was found to bind to the C-terminal end of Per2. Electrophoretic mobility shift assays were used to determine direct binding of OCT-1 to the promoter and chromatine immunoprecipitation validate the interactions in cells. Fluorescence anisotropy and surface plasmon resonance were employed to establish the binding affinity of OCT-1 to the ERa promoter and Per2. OCT-1 was found to have a high affinity for the ERa promoter (∼10 nM). Overall, our data points towards a direct regulation of estrogen receptor signaling by circadian modulators.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2125. doi:10.1158/1538-7445.AM2011-2125
Abstract 2127: The role of FOXD3 in resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells
Authors: Basile Kevin J. , Abel Ethan V. , Aplin Andrew E. 
Published: July 2012

Abstract
Melanoma cells driven by mutant B-RAF are highly resistant to chemotherapeutic treatment. Recent phase I results with PLX4032/RG7204, which selectively inhibits BRAF/MEK/ERK1/2 signaling in mutant B-RAF cells, has given encouragement to this struggling field. Despite initial tumor shrinkage, most responders in the trial experienced tumor relapse over time. Furthermore, 19% of patients failed to show any significant tumor regression. These findings indicate that both intrinsic and acquired resistance will hamper the clinical efficacy of PLX4032. We have previously shown that the stemness factor, FOXD3, is up-regulated following inhibition of mutant B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that up-regulation of FOXD3 after PLX4032 and PLX4720 (the non-clinical tool compound for PLX4032) treatment confers resistance to cell death. siRNA-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032/4720 treatment in mutant B-RAF melanoma cell lines. Additionally, up-regulation of FOXD3 after PLX4720 treatment was attenuated in non-adherent conditions and correlated with enhanced cell death. Ectopic expression of FOXD3 in non-adherent cells significantly reduced cell death in response to PLX4720 treatment. Together, these data indicate that up-regulation of FOXD3 is an adaptive response to B-RAF inhibitors that promotes a state of drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2127. doi:10.1158/1538-7445.AM2011-2127
Abstract 2130: Overcoming chemotherapy resistance by targeting LDHA mediated glycolysis
Authors: Liu Zixing , Zhou Ming , Zhao Yuhua , Yan Ding , Liu Hao , Tan Ming 
Published: July 2012

Abstract
Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells. Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells. LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2130. doi:10.1158/1538-7445.AM2011-2130
Abstract 2136: Expression of fusion proteins in acute myeloid leukemia cells increases sensitivity to histone deacetylase inhibitors
Authors: Petruccelli Luca A. , Rice Kim L. , Pettersson Filippa , Nichol Jessica N. , Skoulikas Sophia , Licht Jonathan D. , Miller Wilson H. 
Published: July 2012

Abstract
Acute myeloid leukemias (AMLs) are often characterized by chromosomal translocations resulting in the expression of fusion proteins (FP). Some FP have been demonstrated to recruit histone deacetylases (HDACs) and repress the expression of DNA repair genes. This may result in an increased sensitivity to histone deacetylase inhibitors (HDI) due to their ability to also down-regulate DNA repair gene expression and induce DNA damage. We have tested the sensitivity of PLZF-RARα, PML-RARα and AML1-ETO inducible cell lines to HDI in order to characterize changes in the mechanisms of cell death.
Treatment of U937 cells with vorinostat results in DNA damage as measured by the COMET assay, followed by cell death. To test the effect of FP expression, U937 cells stably transfected with PLZF-RARα, PML-RARα or AML1-ETO cDNA under the control of a tetracycline-off or a zinc-inducible system were treated with vorinostat and assayed for cell death in the presence/absence of FP. FP expression resulted in increased cell death and caspase-3/7 activation. This effect was found to be largely caspase driven as pre-treatment with the pan-caspase inhibitor Z-VAD-FMK resulted in protection against vorinostat-induced cell death. In addition, FP expressing cells were also exposed to the DNA-targeting agents Doxorubicin, Etoposide, Cisplatin and ionizing radiation. Again, FP expression resulted in increased cell death.
In addition, we investigated the effect of FP expression on vorinostat sensitivity using a PLZF-RARα murine hematopoietic model. A retroviral expression system was used to overexpress PLZF-RARα in lineage-depleted (Lin-) murine hematopoietic progenitors, followed by vorinostat treatment in the absence/presence of PLZF-RARα. The increased sensitivity of FP expressing cells to HDI and DNA-targeting agents suggests a mechanism where the combination of an FP expression and HDI results in an increased accumulation of DNA damage, leading to enhanced cell death.
These findings are significant as they point to FP expressing AMLs as a target group that may respond better to HDI-based therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2136. doi:10.1158/1538-7445.AM2011-2136
Abstract 391: Inflammatory mediators of prostate cancer metastasis
Authors: Martinez-Ferrer Magaly , Qi Ying , Sanchez Maria M. , Bhowmick Neil A. 
Published: July 2012

Abstract
Inflammation has been linked to the initiation and metastatic progression of prostate cancer. We previously reported results showing that CX3CL1 and IL-15 were predominantly down-regulated in prostate cancer patients that develop biochemical recurrence following prostatectomy. This study tests the hypothesis that chemokine biomarkers that predict biochemical recurrence of prostate cancer regulate metastatic progression of the cancer. In order to determine the function of the chemokines, PC3 and LNCaP prostate cancer cell lines were used alone and in combination with conditioned media from prostate stromal cells expressing the chemokines of interest. IL-15 and CX3CL1 cDNAs were subcloned into lentiviral constructs. The lentiviral constructs were transduced into prostate stromal cells developed from wild type C57BL/6 mice. Seventy-two hours conditioned media was used to verify the expression of the respective chemokines by ELISA. The individual prostate cancer cell lines (PC3 and LNCaP) were incubated in the respective stromal conditioned media and characterized for measurable characteristics that promote a cancer cell to be metastatic. In this study we show that IL-15 and CX3CL1 significantly decreased (P&lt;0.0001) PC3 proliferation in vitro. Furthermore, IL-15 and CX3CL1 also had the ability to significantly inhibit migration of PC3 prostate cancer cells in vitro (P&lt;0.01). Introducing IL-15 and CX3CL1 into the stromal microenvironment of the androgent independent PC3 cells significantly increased apoptosis (P&lt;0.05). No significant changes were observed in the androgen dependent LNCaP prostate cancer cells. Our results indicate that IL-15 and CX3CL1 may suppress metastasis in vitro by decreasing proliferation and migration, and increasing apoptosis in the highly metastatic PC3 prostate cancer cell line. The studies will help to enable the dissection of the role of the chemokines on cancer cells in the context of its stromal micronvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 391. doi:10.1158/1538-7445.AM2011-391