bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3807: ER-60 increases cell migration and serves as a prognostic marker of cervical cancer
Authors: Liao Chia-Jung , Lin Yang-Hsiang , Lin Kwang-Huei 
Published: June 2012

Abstract
Cervical cancer is the second most common cancer in women worldwide. Human papilloma virus infection is the primary cause of cervical cancer, although it cannot cause cancer by itself. Molecular markers involved in cervical carcinogenesis are needed. A two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomic strategy was used to discover genes with exceptional expression from four paired cervical cancer tissues. Immunoblotting and immunohistochemical analysis with 52 paired specimens and 107 sections were used to confirm the results of 2-DE, and the clinical significance was estimated. The molecular functions of ER-60 were investigated in vitro and in vivo. We identified ER-60 was upregulated in 71.2% of cancerous tissues. ER-60 expression differed significantly between patients with different histological types and differentiation grades (P = 0.013 and 0.045, respectively). Patients with high ER-60 expression had a lower 5-year overall survival (OS) and recurrence-free survival (RFS) rate (P = 0.038 and 0.017, respectively). High ER-60 expression was an independent prognostic factor of poor RFS (P = 0.019). Knockdown of ER-60 expression in HeLa cell decreased cell motility. The lung metastasis was inhibited when introduced ER-60-knockdown cells into severe combined immunodeficiency mice. We observed accumulation of b-catenin and regulation of b-catenin downstream CD44 and S100A4 expression in ER-60-knockdown cell were responsible for this migration inhibition. Taken together, ER-60 overexpression is a potential prognostic factor of poor OS and an independent factor of poor RFS in cervical cancer. ER-60 may be involved in cervical cancer invasion by modulating b-catenin protein stability and signaling.
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 3807. doi:10.1158/1538-7445.AM2011-3807
Abstract 3814: Signet-ring cell gastric carcinoma has different epigenetic signature from poorly differentiated gastric carcinoma
Authors: Kim Hyun Soo , Park Hong Jun , Yang Misuk 
Published: June 2012

Abstract
Background/Aim: Gastric cancer is divided into differentiated intestinal type and undifferentiated diffuse type by the most widely used Lauren's classification, which appear clearly as dissimilar clinical and epidemiological entities. Undifferentiated diffuse type gastric cancer is also classified into poorly differentiated carcinoma and signet-ring cell carcinoma (SRCC). However, recent evidences suggest early SRCC is an initial, differentiated form of diffuse gastric cancer that may evolve into poorly differentiated carcinoma (PDC). To test the hypothesis that molecular epigenetic signature of SRCC is different from that of PDC in early gastric carcinogenesis, we compared epigenetic methylation profile between SRCC and PDC and found unique epigenetic signature of SRCC. Methods: Six genes (GDNF, ROR-a, KLF7, MINT25, E-cadherin (CDH1), and LINE-1) were identified as sensitive molecular markers of early gastric cancer at a previous study. We evaluated the DNA methylation patterns of 4 gene promoters (GDNF, ROR-a, KLF7 and LINE-1(long interpersed nuclear element-1)) by bisulfite-PCR and pyrosequencing in primary tissues from 33 PDCs and 20 SRCCs as a test group. Then, the methylation status of the 6 genes including MINT25 and E-cadherin (CDH1) was next evaluated in endoscopically biopsied gastric cancer tissues from prospectively collected 21 PDCs and 22 SRCCs as a validation group. Results: In the test group, quantitative methylation levels of 3 genes (GDNF, ROR-a, and LINE-1) of SRCCs were significantly different from those of PDCs. MINT25, E-cadherin including the above 4 genes were next evaluated in the validation group. We confirmed the significant different levels of methylations of prospectively collected SRCCs from PDCs. Compared to PDCs, SRCCs showed the lower level of methylations for GDNF (17.7% vs. 31.0%, p = 0.001) and ROR-a (14.4% vs. 28.0%, p = 0.001) genes. Interestingly, however, the methylation level of E-cadherin was higher in SRCCs than that of PDCs (26.8% vs. 20.5%, p = 0.009). Methylaion levels of LINE-1 (63.0% vs. 60.5%), MINT25 (31.1% vs. 34.3%) and KLF7 (10.2% vs. 18.1%) in SRCCs were not significantly different from those of PDCs. Conclusion: Our results identified unique methylation patterns of SRCCs distinguished from PDCs, suggesting different molecular epigenetic signature of SRCC in gastric carcinogenesis.
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 3814. doi:10.1158/1538-7445.AM2011-3814
Abstract 3822: DNA copy number changes in the PI3K signaling pathway genes in triple negative breast cancer
Authors: Oliveira Marcia C. , Pereira Silma R. , Ribeiro Enilze MF , Lima Rubens S. , Urban Cicero A. , Sebastião Ana Paula M. , Marian Catalin , Haddad Bassem R. , Cavalli Iglenir J. , Cavalli Luciane R. 
Published: June 2012

Abstract
Background: Triple negative breast cancer (TNBC) is associated with poor prognosis and a high mortality rate when compared to the other breast cancer subtypes. These tumors lack the expression of ER, PR and HER2 receptors, and do not respond well to the currently available adjuvant therapies. The phosphatidylinositol 3-kinase (PIK3) signaling pathway mediates key cellular functions. Alterations of genes in this pathway have been shown to predict responsiveness to cancer targeted therapies. In this study, five genes involved in this signaling pathway, PIK3CA, AKT1, AKT2, PTEN and FGFR, were evaluated for DNA copy number changes in two sets of TNBC specimens.
Methods: TNBC samples were obtained from the Hospital Nossa Senhora das Gracas, Curitiba, PR, Brazil. Two sets of TNBC samples were analyzed: the first set was composed of 30 formalin fixed-paraffin embedded tissue specimens and were analyzed for the PIK3CA, AKT1, AKT2, PTEN and FGFR genes by FISH. Locus-specific probes were prepared from BAC contigs for each gene and a centromeric probe for chromosome 3 was used as a control for copy number. The second set was composed of 17 frozen samples and were analyzed by array-CGH using a 44K-Agilent array platform. Real-Time PCR (TaqMan assay), was used to validate the array-CGH data for the above five genes.
Results:
FISH: PTEN loss and FGFR3 amplification were the most common findings occurring in 56% and 41% of the TNBC samples respectively. PIK3CA, AKT2 and AKT1 were amplified in 31%, 25% and 9.5% of the samples respectively.
Array-CGH/Real time PCR: DNA copy number changes were observed by array-CGH in all, but one TNBC sample. The gene with highest frequency of amplification detected by array-CGH was PIK3CA (amplified in 77% of the cases). These findings were confirmed in 70% of the cases. FGFR2, AKT2 and PTEN were amplified in 35%, 24% and 24% of the cases respectively, These findings were confirmed for FGFR2 in 83% of the samples and for PTEN in all the samples. AKT2 amplification was only confirmed in 25% of the samples. Finally AKT1 was observed amplified in by array-CGH in 6% of the cases, which was confirmed by Real-time PCR.Conclusions: Based on our initial results, we conclude that TNBC presents DNA copy number alterations in genes involved in the PIK3 signaling pathway. Upon validation of these alterations in a larger number of cases, with correlation to prognostic parameters, their potential use as therapeutic targets can be considered for further investigation.
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 3822. doi:10.1158/1538-7445.AM2011-3822
Abstract 3834: 3-ethynyl-1H-indazoles as inhibitors of PI3k signaling pathway
Authors: Barile Elisa , De Surya , Carlson Coby B. , Chen Vida , Knutzen Christine , Riel-Mehan Megan , Dahl Russell , Chiang Gary , Pellecchia Maurizio 
Published: June 2012

Abstract
A new series of 3-ethynyl-1H-indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1 and mTOR kinases. Combination of computational modeling and structure-activity relationships studies reveal a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays anti-proliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could result useful in deriving novel selecting and multi-kinase inhibitors for clinical use.
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 3834. doi:10.1158/1538-7445.AM2011-3834
Abstract 3839: Wild-type p53 induced protein phosphatase (Wip1) inhibits the proapoptotic function of JNK and p38 MAPK in prostate cancer cells
Authors: Song Ji Young , Young Park Ji , Hye Kim Ga , Choi Jene 
Published: June 2012

Abstract
The mechanism regulating radiation-induced anti-apoptotic response in prostate cancer cell lines is not clear yet. Wip1 is the major member of the Ser/Thr PP2C family that dephosphorylates and inactivates p38 MAPK, p53, chk1, Mdm2 and ATM. Here we provide Wip1 was negative regulator of γ-radiation-mediated apoptotic response in LNCaP cells. The levels of Wip1 were increased after exposed to γ-radiation and induced Wip1 repressed cell death. Wip1 depletion with siRNA resulted in increased apoptotic cell death in LNCaP cells, which was not observed in radiation-sensitive HeLa cells. Radiation-induced Wip1 induction was inversely co-related with the decrease of phospho-JNK and -p38 MAPK in LNCaP cells, indicating that Wip1 is a negative regulator of JNK and p38 MAPK pathways. Furthermore, in response to γ-radiation, Bax proteins are increased and directly interact with Wip1. The data suggest that Wip1 may be a central player on the mechanism of radio-resistance in LNCaP cells. Currently, we are investigating the role of Wip1 in BAX-mediated apoptotic cell death.
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 3839. doi:10.1158/1538-7445.AM2011-3839
Abstract 3840: Rap1 GTPase activating protein (Rap1GAP) is downregulated in DCIS and invasive ductal carcinoma
Authors: Rhee Sarah S. , Lim Bora , Kim Hyoung-ha , Wang Yan , Aziz Usman , Butt Usman , Tang Waixing , Vuchak Lisa A. , DeMichele Angela , Troxel Andrea B. , Feldman Michael D. , Meinkoth Judy L. , Brose Marcia S. 
Published: June 2012

Abstract
Introduction: Rap1 and Rap2, both small GTPases of the Ras family, serve as crucial regulators in cell polarity, adhesion, migration, and lumen formation via crosstalk with cytoskeletal proteins. Rap1 GTPase activating protein (Rap1GAP), which negatively regulates Rap1 and Rap2 activity, has found to be downregulated in multiple cancers, including oropharyngeal squamous cell carcinoma, melanoma, papillary and follicular thyroid carcinoma, and colorectal carcinoma but has not yet been studied in breast cancer. In order to determine if Rap1GAP downregulation plays a role in breast cancer formation, we decided to expand our prior work to study its expression in breast cancer tissue.
Methods: Twenty-one formalin-fixed paraffin-embedded human tissue blocks were selected on the basis that they contained normal breast tissue and either adjacent breast ductal carcinoma in situ (DCIS) or invasive ductal carcinoma. Using immunohistochemistry, we assessed the expression of Rap1GAP. We also assayed two human breast cancer cell lines with different levels of invasiveness, MCF7 (non-invasive) and MDA-MB-231 (invasive), to determine different levels of Rap1GAP expression and subsequent changes in Rap1 and Rap2 expression and activity.
Results: Rap1GAP expression in both DCIS and invasive ductal carcinoma were found to be decreased compared to adjacent normal breast tissue. However, Rap1GAP expression was not statistically different between DCIS and invasive carcinoma lesions. Rap1GAP was found to be expressed highly in MCF7 but not in MDA-MB-231 cells. Moreover, only MDA-MB-231 cells exhibited high basal Rap2 activity. Activated Rap1 (RAP1-GTP) was not detected in either line.
Conclusion: Our findings suggest that loss of Rap1GAP occurs as an early event in breast cancer tumorigenesis with a significant decrease in the transition from normal to DCIS, with a possible further decrement in the DCIS to invasive transition. Interestingly, while Rap1 and Rap2 were expressed in non-invasive and invasive cell lines, loss of Rap1GAP in the invasive cell line was associated with increase in active Rap2, but not active Rap1. These findings suggest that as in other cancers, loss of Rap1GAP may contribute to the invasive phenotype and thus further investigation is warranted.
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 3840. doi:10.1158/1538-7445.AM2011-3840
Abstract 3850: CDKN2a deficiency exposes a requirement for RhoA in maintenance of non-small cell lung cancer
Authors: Konstantinidou Georgia , Torti Francesca , Batten Kimberly , Minna John D. , Shay Jerry W. , Scaglioni Pier Paolo 
Published: June 2012

Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death world-wide. Tumorigenesis is a multistep process that involves several genetic aberrations. For example, K-RAS (onc-K-RAS), the most commonly mutated oncogene in human cancer, is expressed in about 25% of NSCLC. In addition, NSCLC often carry mutations or epigenetic modifications that affect the expression of the CDKN2a locus, which comprises the p16INK4a and the p14ARF (p19ARF in mice) tumor suppressor genes, which in turn regulate the retinoblastoma and the p53 tumor suppressor pathways.
NSCLC tumorigenesis is faithfully recapitulated in transgenic mice where onc-K-Ras expression invariably induces adenomas and, after a long latency, adenocarcinomas. To characterize the consequence of concomitant onc-K-RAS expression and CDKN2a inactivation, we generated p16CDK4/p19ARF null mice expressing onc-K-Ras in the respiratory epithelium.
We determined that Cdkn2a deficiency promotes rapid progression of lung adenomas to adenocarcinomas, which display aggressive features. We determined the status of activation of oncogenic signaling networks downstream of onc-K-Ras with phosphospecific antibodies and by expression profiling. We discovered that NSCLC that arises in CDKN2A deficient mice display dysregulation of RhoA, a small GTPase implicated in the regulation of the cytoskeleton, cell adhesion, and motility of cancer cells in culture. These activities are pertinent to tumorigenesis, however it is not known whether RhoA plays a role in the maintenance of established tumors.
Surprisingly, we determined that RhoA is required for the survival of NSCLC derived lines expressing onc-K-RAS and deficient for either INK4a or the p53 tumor suppressor both when cultured in vitro and as xenografts in vivo. Cell death was due to a proapoptotic program and was accompanied by disruption of the cytoskeleton. Moreover, by performing loss and gain of function experiments we identified focal adhesion kinase (FAK) protein as the principal downstream target of RhoA responsible for this effect. Experiments in vivo with specific inhibitors are ongoing and will be presented at the meeting.
Our findings reveal a previously unappreciated context dependent requirement of the RhoGTPase to maintain viability of established NSCLC. We propose that RhoA and its signaling network are novel therapeutic targets in NSCLC.
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 3850. doi:10.1158/1538-7445.AM2011-3850
Abstract 3851: The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate RhoB-mediated cell death after DNA damage
Authors: Srougi Melissa C. , Burridge Keith 
Published: June 2012

Abstract
Commonly used antitumor treatments, including radiation and chemotherapy, function by damaging the DNA of rapidly proliferating cells. However, resistance to these agents is a predominant clinical problem. A member of the Rho family of small GTPases, RhoB has been shown to be integral in mediating cell death after ionizing radiation (IR) or other DNA damaging agents in Ras-transformed cell lines. In addition, RhoB protein expression increases after genotoxic stress, and loss of RhoB expression causes radio- and chemotherapeutic resistance. However, the signaling pathways that govern RhoB-induced cell death after DNA damage remain enigmatic. Here, we show that RhoB activity increases in human breast and cervical cancer cell lines after treatment with DNA damaging agents. Furthermore, RhoB activity is necessary for DNA damage-induced cell death, as the stable loss of RhoB protein expression using shRNA partially protects cells and prevents the phosphorylation of c-Jun N-terminal kinases (JNKs) and the induction of the pro-apoptotic protein Bim after IR. The increase in RhoB activity after genotoxic stress is associated with increased activity of the nuclear guanine nucleotide exchange factors (GEFs), Ect2 and Net1, but not the cytoplasmic GEFs p115 RhoGEF or Vav2. Importantly, loss of Ect2 and Net1 via siRNA-mediated protein knock-down inhibited IR-induced increases in RhoB activity, reduced apoptotic signaling events, and protected cells from IR-induced cell death. Collectively, these data suggest a mechanism involving the nuclear GEFs Ect2 and Net1 for activating RhoB after genotoxic stress, thereby facilitating cell death after treatment with DNA damaging agents.
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 3851. doi:10.1158/1538-7445.AM2011-3851
Abstract 3863: Exhaled microRNAs as potential biomarkers in lung cancer
Authors: Shi Miao , Han Weiguo , Spivack Simon 
Published: June 2012

Abstract
Introduction: There is a need for non-invasive airway-based biomarkers in lung carcinogenesis for both diagnosis, and risk assessment. MicroRNAs are small, stable, noncoding RNAs that function in gene regulation. Recent studies have revealed that microRNAs play important regulatory roles in carcinogenesis. Exhaled breath condensate (EBC) contains airway lining fluid molecules, including nucleic acids, as we've previously reported for DNA methylation. We previously developed an RNA-specific microRNA-PCR, whereby PCR artifact can be detected. Here we pilot the detection of microRNAs in EBC of lung cancer patients and controls. Methods: MicroRNA expression profiling using RNA-specific RT-qPCR was performed in EBC from 28 subjects, choosing literature-derived microRNAs that segregate tumors and non-tumor tissue, and an ongoing discovery effort we have commenced using microRNA-seq for tumor versus non-tumor comparison. As of abstract deadline, the top 12 significantly different microRNAs between lung tumor and non-tumor were chosen and their qPCR primers were designed. Results: So far, we have detected several microRNAs in EBC including 21, 34a, 153, 193b, 200c, 221; case-control comparisons are pending. Topographic validation studies are pending. Conclusion: By comparing the differences of microRNA expression between EBC from lung cancer cases and EBC from non-cancer controls, potential exhaled microRNA biomarkers might be found and used in early detection of lung cancer.
This work was supported by National Institutes of Health grants1RC1 CA145422-01, 1K24-CA139054-01.
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 3863. doi:10.1158/1538-7445.AM2011-3863
Abstract 3870: Improved PCR amplification of DNA biomarkers with the use of chimeric oligonucleotides
Authors: Millholland John M. , Patel Sheryl G. , Shuber Anthony P. 
Published: June 2012

Abstract
Methylation of the Twist1 gene has been linked to various cancers, including bladder cancer. We are developing a non-invasive diagnostic assay utilizing urinary protein and DNA biomarkers, including Twist1, as triage monitors in high-risk bladder cancer populations. Since final clinical assay performance is dependent on the optimal technical performance of each individual marker, we incorporated the use of chimeric PCR primers to establish PCR conditions for all DNA markers that would greatly simplify the process of optimizing PCR performance.
Amplification of difficult DNA templates can involve significant optimization of PCR conditions, and is often complicated by mispriming and other non-specific amplification events. The chimeric primers we designed have a variable 3’ target-specific sequence, and a common 22 nucleotide 5’ sequence that is unrelated to any human DNA. The common 5’ sequence generates similar melting temperatures for all primers (Tm 68-72oC) that permits uniform PCR conditions regardless of the characteristics of the template specific sequence. In addition, the chimeric primers permit a higher annealing temperature, which minimizes non-specific PCR amplification.
In the study described here, conventional methylation specific primers were designed against a highly methylated region of the Twist1 promoter with and without the 5’ chimeric DNA sequence, and PCR conditions were optimized for each primer pair. Performance was assessed using DNA isolated from 50 bladder cancer tissues. After bisulfite conversion, PCR amplifications were carried out using the Bio-Rad C1000 platform and subsequently analyzed by agarose gel electrophoresis. Using traditional primers, Twist1 sensitivity was comparable to previous reports (68%, Renard et al, 2010), whereas using the chimeric primers, sensitivity increased to 90%.
Incorporation of chimeric primers greatly simplifies PCR optimization and permits the use of higher annealing temperatures, resulting in higher specificity. We have applied this method to the detection of Twist1 methylation in bladder cancer tissues and demonstrate significant improvement in performance, when compared to traditional, non-chimeric oligonucleotide primers. In addition, this primer modification can be applied to multiple assay formats and DNA targets to improve sensitivity for use in non-invasive diagnostic assays, where mutant DNA is expected to be limiting.
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 3870. doi:10.1158/1538-7445.AM2011-3870