bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3803: Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells
Authors: Liu Chun-Yu , Su Jung-Chen , Tseng Ling-Ming , Chu Pei-Yi , Tai Wei-Tien , Shiau Chung-Wai , Chen Kuen-Feng 
Published: May 2015

Abstract
Background: Interfering the oncogenic STAT3 signaling is considered as promising anti-cancer strategy. Previously, we have reported an obatoclax analogue, SC-2001, as a novel STAT3 inhibitor in hepatocellular carcinoma cells (Cancer Letter 2012). Here, we examined the efficacy and drug mechanism of SC-2001 in breast cancer cells.
Methods: Human breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT assay. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Small interference RNA was used to knockdown SHP-1. Quantitative RT-PCR was used for assessing gene transcription. In vivo efficacy of SC-2001 was tested in xenografted nude mice.
Results: SC-2001 inhibited cell growth and induced apoptosis in breast cancer cell lines (MDA-MB-468, MDA-MB-231, MDA-MB-453, MCF-7 and HCC 1937). SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited its transcriptional activities in a dose-dependent manner. STAT3-regulated proteins, including Mcl-1, survivin and cyclin D1, were also repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of SHP-1, a negative regulator of STAT3, in a time-dependent manner. The enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription. Furthermore, co-immunoprecipitation experiment showed that SC-2001 upregulated SHP-1 expression through enhanced transcription by RFX-1 transcription factor. Importantly, SC-2001 showed efficacious antitumor activity and p-STAT3 downregulation in MDA-MB-468 xenograft tumors.
Conclusion: Our results suggest that SC-2001 induced apoptosis in breast cancer cells, and that this effect is mediated through RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation.
(Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006, NSC-102-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4)
Citation Format: Chun-Yu Liu, Jung-Chen Su, Ling-Ming Tseng, Pei-Yi Chu, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen. Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2014-3803
Abstract 3804: CPA-7, an inhibitor of STAT3, is a potent tumoricidal agent in peripheral tumor models and is impermeable to the CNS
Authors: Assi Hikmat , Paran Chris , Savakus Jon , Hoeschle James , Raptis Leda , Lowenstein Pedro R. , Castro Maria G. 
Published: May 2015

Abstract
Analogues of the prototypical cancer drug cisplatin number by the hundreds with variable effects on DNA and signal transduction. Of these compounds, CPA-7 has been shown to elicit potent tumoricidal activity by preferentially targeting STAT3 in transformed cells. In this study, we characterized the response of rodent and human glioma cells to STAT3 inhibition by CPA-7. In addition, we determined if CPA-7 administration is sufficient for the induction of tumor regression in intracranial and peripheral mouse tumor models. Cultured glioma cells treated with CPA-7 ceased to proliferate and underwent apoptosis. Induction of apoptosis was associated with reduction of phosphorylated STAT3 and downstream transcriptional products such as cyclin D, survivin, and Bcl-xl. Although CPA-7 inhibits STAT3 preferentially, we observed an inhibition of STAT1 at doses higher than 30uM. Furthermore, mice bearing GL26 flank tumors underwent complete tumor regression in response to CPA-7 administration. This potent therapeutic effect of CPA-7 could not be duplicated in mice bearing intracranial GL26 brain tumors as that group became moribund at the same time as vehicle treated mice. Western blot and immunohistochemistry analysis of tumors isolated from CPA-7 treated mice demonstrated a reduction of phosphorylated STAT3 in peripheral but not intracranial tumors. This data suggests that CPA-7 is impermeable to the brain as a consequence of its molecular structure. Permeability measurements of CPA-7 using the PAMPA assay support this notion. These observations were corroborated in the B16-f0 and B16-f10 mouse melanoma models. Inhibition of STAT3 has been shown to be an effective strategy at inducing tumor regression in multiple cancer types. Although the discovery of effective and specific inhibitors has been limited, we believe that CPA-7 is a compound with potential therapeutic activity for peripheral solid tumors and warrants further evaluation and pharmacological characterization.
Supported by NIH/NINDS
Citation Format: Hikmat Assi, Chris Paran, Jon Savakus, James Hoeschle, Leda Raptis, Pedro R. Lowenstein, Maria G. Castro. CPA-7, an inhibitor of STAT3, is a potent tumoricidal agent in peripheral tumor models and is impermeable to the CNS. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3804. doi:10.1158/1538-7445.AM2014-3804
Abstract 3805: Anticancer agent HJC0416 inhibits the growth of breast cancer xenografts via downregulating STAT3 signaling
Authors: Xiong Ailian , Chen Haijun , Yang Zhengduo , Cai Guoshuai , Wang Lili , Ding Chunyong , Xu Grace G. , Wild Christopher , Ye Na , Uray Ivan P. , Zhou Jia , Shen Qiang 
Published: May 2015

Abstract
Signal transducers and activators of transcription (STATs) play important roles in regulating the expression of genes activated during tumorigenesis. Particularly, STAT3 has been shown to contribute significantly in breast carcinogenesis and is often overexpressed in primary breast tumors. Increased STAT3 transcriptional activity is correlated with ER-negative phenotype in breast cancer cell lines and in primary invasive ductal breast carcinomas. Therefore, STAT3 emerges as a promising target for breast cancer treatment and prevention. We have designed, synthesized and screened a series of novel STAT3 inhibitors utilizing fragment-based drug design strategy. A number of small molecules with novel scaffolds have been discovered with low-micromolar to nanomolar potency in inhibiting the proliferation of various human breast cancer and pancreatic cancer cells. The identified compound HJC0416 significantly suppresses STAT3 promoter activity and STAT3 phosphorylation, reduces total STAT3 protein expression, induces cell growth arrest and early apoptosis in triple-negative breast cancer cell line MDA-MB-231. HJC0416 also demonstrated a better efficacy in suppressing the growth of MDA-MB-231 breast xenograft tumors via intraperitoneal and oral administrative routes, with remarkably improved aqueous solubility and less toxicity than the lead compounds. We further demonstrated that p70S6K and MAPK pathways mediate the inhibitory effects from HJC0416 via downregulating RPS6, PDCD4 and EEF2K proteins. In conclusion, the new anticancer agent HJC0416 inhibits the growth of breast cancer xenografts via suppressing STAT3 expression and its phosphorylation.
Citation Format: Ailian Xiong, Haijun Chen, Zhengduo Yang, Guoshuai Cai, Lili Wang, Chunyong Ding, Grace G. Xu, Christopher Wild, Na Ye, Ivan P. Uray, Jia Zhou, Qiang Shen. Anticancer agent HJC0416 inhibits the growth of breast cancer xenografts via downregulating STAT3 signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3805. doi:10.1158/1538-7445.AM2014-3805
Abstract 381: Characterizing the role of heterochromatin protein 1 gamma in normal intestinal homeostasis and tumorigenesis
Authors: Lio Ka Ian , Clarke Alan , Reed Karen 
Published: May 2015

Abstract
Background: Epigenetic modifications are being increasingly recognized to contribute to colorectal cancer formation. Heterochromatin Protein 1 gamma (HP1gamma) has an important role in carcinogenesis and tumorigenesis by regulating several mechanisms, such as heterochromatin formation, gene silencing and DNA replication and repair. The aim of this study was to characterize the role of HP1gamma in normal intestinal homeostasis, tumorigenesis and cancer progression.
Methods: The Cbx3 gene (encoding the HP1gamma protein) was conditionally deleted in the murine small intestinal epithelium under normal intestinal homeostasis and in the context of aberrant Wnt signaling using transgenic mouse models. Furthermore, the effect of CBX3 depletion on Wnt activation was investigated using an in vitro system.
Results: The level of Cbx3 was significantly up-regulated in small intestinal cancer tissues of mouse models, consistent with our preliminary observations that CBX3 was highly expressed in tumor samples of colorectal cancer patients compared to matched normal tissues. We found a dramatic increase in the lifespan of our colorectal cancer mouse model following the loss of Cbx3. Both in vivo and in vitro studies demonstrated that depletion of Cbx3 leads to decreased transcription of a subset of Wnt target genes and Wnt signaling activity, respectively. Furthermore, marked epigenetic alternations were observed in association patterns of HP1gamma and the heterochromatin markers (H3K9me2, H3K9me3 and H4K20me3) in wild-type and mouse model of colorectal cancer.
Conclusions: HP1gamma may play direct or indirect roles in regulating Wnt target gene expression by binding H3K9me3 or H4K20me3 and altering heterochromatin formation. These data provide stepping stones for further investigation of the mechanistic role of HP1gamma in normal intestinal homeostasis, tumor initiation and progression.
Citation Format: Ka Ian Lio, Alan Clarke, Karen Reed. Characterizing the role of heterochromatin protein 1 gamma in normal intestinal homeostasis and tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 381. doi:10.1158/1538-7445.AM2014-381
Abstract 3820: Expression of ST6Gal-1 in colorectal cancer and patient prognosis
Authors: Jadhav Trafina , Narang Saksham , Bae Jeehyun , Schultz Matthew , Eltoum Isam-Eldin , Bellis Susan , Bae Sejong , Manne Upender 
Published: May 2015

Abstract
Background: ST6Gal-1 sialyltransferase, a type II membrane protein that catalyzes the transfer of sialic acid to the N-glycans of certain receptors, is upregulated in several cancers, including colorectal cancers (CRCs), and its levels correlate with metastatic potential. Therefore, we investigated its prognostic value in CRCs.
Methodology: Formalin-fixed, paraffin-embedded CRC tissues from African Americans (Blacks) (n=50) and non-Hispanic Caucasians (Whites) (n=51) patients were evaluated for immunohistochemical (IHC) expression of ST6Gal-1. IHC expression was assessed using an anti-human ST6Gal-1 polyclonal antibody (R&D Systems) with antigen retrieval. The antibody-antigen complex was detected by the Immpact NovaRed system (Vector Labs). A semiquantitative immunostaining scoring system (ISS) on a scale of 0-4 was developed to assess the ST6Gal-1 expression, and a cutoff value (1.2 ISS) was determined by the bootstrap method. This value was used to classify tumors as low- or high-ST6Gal-I expressors. Previously, these tissues were evaluated for p53 nuclear accumulation (p53nac), an indicator of abnormal p53, by IHC. ST6Gal-1 expression levels were correlated with demographic and clinicopathologic features and with patient survival.
Results: Increased ST6Gal-1 expression was observed in all CRCs as compared to their corresponding normal tissues. The overall frequency of CRCs with increased ST6Gal-1 expression was 80%; it was more commonly found in Blacks (88%, 44 of 50) than in Whites (70%, 36 of 51) (X2 p=0.031). Also, increased expression was associated with p53nac, and ST6Gal-1 expression was higher in CRCs that exhibited p53nac (87%, 42 of 48) relative to CRCs without p53nac (70%, 35 of 50) (X2 p = 0.034). Moreover, patients with CRCs with high ST6Gal-1 had lower median survival (29.3 months) relative to those with low ST6Gal-1 expression (58.5 months).
Conclusions: These preliminary findings suggest that increased expression of ST6Gal-1 expression, found predominantly in Blacks patients and in CRCs with abnormal p53, is associated with poor patient survival.
Citation Format: Trafina Jadhav, Saksham Narang, Jeehyun Bae, Matthew Schultz, Isam-Eldin Eltoum, Susan Bellis, Sejong Bae, Upender Manne. Expression of ST6Gal-1 in colorectal cancer and patient prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3820. doi:10.1158/1538-7445.AM2014-3820
Abstract 3826: Breast cancer metastasis suppressor-1 promoter methylation in cell free DNA provides prognostic information in non-small cell lung cancer
Authors: Balkouranidou Ioanna , Chimonidou Maria , Milaki Georgia , Tsaroucha Emily , Kakolyris Stelios , Welch Danny , Georgoulias Vasilis , Lianidou Evi 
Published: May 2015

Abstract
Background: Breast-cancer metastasis suppressor 1 (BRMS1) gene encodes for a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without blocking orthotopic tumor growth. The aim of the present study was to evaluate for the first time the prognostic significance of BRMS1 promoter methylation in cell free DNA (cfDNA) circulating in plasma of non-small cell lung cancer (NSCLC) patients. Towards this goal, we examined the methylation status of BRMS1 promoter in NSCLC tissues, matched adjacent non-cancerous tissues and corresponding cfDNA as well as in an independent cohort of patients with advanced NSCLC and healthy individuals.
Methods: BRMS1 promoter methylation was examined in 57 NSCLC tumors and adjacent non-cancerous tissues, in cfDNA isolated from 48 corresponding plasma samples, in cfDNA isolated from plasma of 74 patients with advanced NSCLC and 24 healthy individuals.
Results: BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and corresponding cfDNA (47.9%) but not in cfDNA from healthy individuals ( 0%), while it was also highly methylated in cfDNA from advanced NSCLC patients (63.5%). In operable NSCLC, Kaplan-Meier estimates were significantly different in favor of patients with non-methylated BRMS1 promoter in cfDNA, concerning both DFI (p=0.048) and OS (p=0.007). In advanced NSCLC, OS was significantly different in favour of patients with non-methylated BRMS1 promoter in their cfDNA (p=0.003). Multivariate analysis confirmed that BRMS1 promoter methylation has a statistical significant influence both on operable NSCLC patients' DFI time and OS and on advanced NSCLC patients' PFS and OS.
Conclusions: BRMS1 promoter methylation in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumor biomarker.
Citation Format: Ioanna Balkouranidou, Maria Chimonidou, Georgia Milaki, Emily Tsaroucha, Stelios Kakolyris, Danny Welch, Vasilis Georgoulias, Evi Lianidou. Breast cancer metastasis suppressor-1 promoter methylation in cell free DNA provides prognostic information in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3826. doi:10.1158/1538-7445.AM2014-3826
Abstract 3827: Predictions for recurrence of non-muscle invasive bladder cancers by circulating miRNAs
Authors: Lin Shu-Hong , Lian Jie , Ye Yuanqing , Dinney Colin P. , Wu Xifeng 
Published: May 2015

Abstract
Background: Circulating microRNAs (miRNAs) have been extensively associated with disease conditions, and shown to be involved in tumorigenesis. In the current study, we aimed to identify miRNAs which are present specifically in the serum of non-muscle invasive bladder cancer (NMIBC) patients and correlate these miRNAs with clinical outcomes. Method: A pilot study was first conducted to profile the expression of 754 miRNAs using the Taqman® microRNA Array and identified 89 miRNAs that can be detected at high levels in more than 30% of samples. In this study, we applied a two-stage design with discovery phase of 280 cases followed by the validation phase of 276 cases using the Fluidigm BioMark™ System to assess whether these 89 miRNAs were associated with bladder cancer clinical outcomes. Results: Among 280 cases in the discovery phase, 134 recurrence events were observed. Further stratification by treatment showed that 147 patients received Bacillus Calmette-Guerin (BCG) treatment and 78 patients received transurethethral resection only (TUR). COX regression on dichotomized expression of miRNAs revealed that 2 and 6 miRNAs were associated with recurrence in the BCG group and the TUR group with p-values &lt;0.05, respectively. The most significant observed association with recurrence had p-values of 0.008(BCG) and 0.005 (TUR). We constructed risk scores for recurrence using previous miRNAs identified by COX regression. Patients with high risk scores had significantly shorter recurrence-free survival in BCG group (p=0.006, mean survival time 9.04 and undefined for high risk and low risk scores) but not in TUR group possibly due to small sample size (p=0.114, mean survival time 4.60 and 14.04). We are in the progress of further verifying associations between candidate miRNAs and clinical outcomes in an additional 276 NIMBC samples. Conclusion: Our preliminary results demonstrate the potential of miRNAs as predictive markers for NMIBC recurrence.
Citation Format: Shu-Hong Lin, Jie Lian, Yuanqing Ye, Colin P. Dinney, Xifeng Wu. Predictions for recurrence of non-muscle invasive bladder cancers by circulating miRNAs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3827. doi:10.1158/1538-7445.AM2014-3827
Abstract 386: Epigenome-wide association study to predict breast cancer risk in European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
Authors: Ambatipudi Srikant , Chajes Veronique , Calvez-Kelm Florence Le , Cuenin Cyrille , Durand Geoffroy , Romieu Isabelle , Herceg Zdenko 
Published: May 2015

Abstract
Aberrant DNA methylation (DNAm) in blood has been used as an epigenetic marker of cancer risk although, the significance of DNAm changes in surrogate tissues as a marker of predicting breast cancer risk remains elusive. This may be potentially accounted by the fact that there are very few study cohorts to understand the significance of DNA methyation prospectively. We examined the potential of DNAm in peripheral blood as a marker of breast cancer risk in a nested case-control cohort of European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study cohort involved 451 female incident breast cancer cases and matched controls (matched for center, age, date of blood collection and menopausal status). Majority of breast cancer cases were localized (47%) and receptor positive (83.1%) while a smaller proportion of samples were metastatic (14%) and 20% of the cases were triple negative. Methylation levels were measured across 485,777 CpG sites using the Illumina HumanMethylation 450K BeadChip array. The cross-reactive probes and polymorphic CpGs were filtered during the analysis. Methylation values for all the probes thus obtained were compared between cases and matched controls using logistic regression model with adjustments for potential confounders. We found differential methylation across 185 probes (P&lt;0.0005) and we believe that these probes may serve as potentially useful surrogate markers for identification of individuals with a high risk of breast cancer development. We are currently verifying and validating these findings in our study cohort and the findings will be discussed at the meeting.
Citation Format: Srikant Ambatipudi, Veronique Chajes, Florence Le Calvez-Kelm, Cyrille Cuenin, Geoffroy Durand, Isabelle Romieu, Zdenko Herceg. Epigenome-wide association study to predict breast cancer risk in European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 386. doi:10.1158/1538-7445.AM2014-386