bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract POSTER-BIOL-1333: TRIP6 regulates p27KIP1 to promote ovarian tumorigenesis
Authors: Lin Fang-Tsyr , Lin Victor T. G. , Lin Vivian Y. , Lai Yun-Ju , Chen Chen-Shan , Liu Kang , Lin Weei-Chin 
Published: August 2015

Abstract
Although the nuclear p27KIP1 functions as a negative regulator of G1/S cell cycle progression by binding to and inhibiting cyclin-CDK complexes, the cytosolic p27KIP1 has been shown to promote adhesion disassembly and tumor invasion. Loss of nuclear p27KIP1 and cytosolic mislocalization of p27KIP1 are frequently found during cancer progression, and these events correlate with poor clinical outcome in many types of cancers, including ovarian cancer. However, the mechanisms underlying this dysregulation are not yet fully understood.
TRIP6 is an adaptor protein that is highly expressed in ovarian serous cystadenocarcinoma. It serves as a platform to recruit a number of molecules, such as NF-κB p65, c-Src, p130cas, Crk, LPA2 and Fas/CD95 receptors, to promote cell motility and antiapoptotic signaling. Using an ovarian cancer xenograft mouse model, we find that TRIP6 knockdown significantly reduces ovarian tumor proliferation. We determine that this effect is in part through the regulation of p27KIP1. Our data show that TRIP6 serves as a bridge to promote the recruitment of p27KIP1 to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT, and facilitates AKT-mediated recognition and phosphorylation of p27KIP1 specifically at T157, thereby promoting the cytosolic mislocalization of p27KIP1. This is required for p27KIP1 to enhance LPA-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27KIP1 expression through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in ovarian cancer xenografts restores nuclear p27KIP1 expression and impairs tumor proliferation. Since the expression of TRIP6 and the activity of AKT are significantly higher in ovarian cancer, restoring the expression of nuclear p27KIP1 and inhibiting the migratory effect of phospho-T157-p27KIP1 by targeting TRIP6 may prove to be an effective approach to reduce ovarian cancer progression.
Citation Format: Fang-Tsyr Lin, Victor T. G. Lin, Vivian Y. Lin, Yun-Ju Lai, Chen-Shan Chen, Kang Liu, Weei-Chin Lin. TRIP6 regulates p27KIP1 to promote ovarian tumorigenesis [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1333.
Abstract POSTER-BIOL-1335: Threonyl-tRNA synthetase overexpression correlates with angiogenesis and progression of human ovarian cancer
Authors: Wellman Theresa L. , Eckenstein Midori , Wong Cheung , Rincon Mercedes , Ashikaga Takamaru , Mount Sharon L. , Francklyn Christopher S. , Lounsbury Karen M. 
Published: August 2015

Abstract
Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. There is growing evidence that tRNA synthetases have a role in cell signaling separate from their function in protein synthesis. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic activity. Exploration of protein and mRNA databases further showed a connection between TARS expression and ovarian cancer. The objective of this study was to test the hypothesis that TARS is secreted by ovarian cancer cells and that its expression in clinical samples correlates with angiogenic markers and ovarian cancer progression. TARS secretion by SKOV3 human ovarian cancer cells was induced by hypoxia or tumor necrosis factor-α (TNF-α) as detected by ELISA and Western blot of culture media (p&lt;0.001). For the clinical study, TARS, vascular endothelial growth factor (VEGF) and PECAM were assessed by immunohistochemistry in serial sections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12 control patients. Serum samples from 31 tissue-matched patients were analyzed by ELISA for TARS, CA125, and tumor necrosis factor-α (TNF-α). There was a strong association between the tumor expression of TARS and advancing stage of epithelial ovarian cancer (p&lt;0.001). TARS expression and localization were also correlated with VEGF (p&lt;0.001). A significant proportion of samples included heavy TARS staining of infiltrating leukocytes which also correlated with stage (p=0.017). Patient serum TARS was related to tumor TARS and angiogenic markers, but did not achieve significance with respect to stage. Multivariate Cox proportional hazard models revealed a surprising inverse relationship between TARS expression and mortality risk in late stage disease (p=0.062). Together these results show that TARS is secreted in response to cell stress and that its expression is increased in epithelial ovarian cancer according to stage and angiogenic progression. These findings and the association of TARS with disease survival provide clinical validation that TARS is associated with angiogenesis in ovarian cancer. These results encourage further study of TARS as a regulator of the tumor microenvironment and possible target for diagnosis and/or treatment in ovarian cancer.
Citation Format: Theresa L. Wellman, Midori Eckenstein, Cheung Wong, Mercedes Rincon, Takamaru Ashikaga, Sharon L. Mount, Christopher S. Francklyn, Karen M. Lounsbury. Threonyl-tRNA synthetase overexpression correlates with angiogenesis and progression of human ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1335.
Abstract POSTER-BIOL-1348: No association between PARK2 and BRCA1-associated gynecologic cancers
Authors: Walsh Christine , Nassanian Hoorig , Agadjanian Hasmik , Miller Carl , Orsulic Sandra , Karlan Beth 
Published: August 2015

Abstract
Purpose of study: We sought to identify genomic modifiers of gynecologic cancer penetrance in BRCA1 185delAG mutation carriers. In a pilot study using the Illumina 610K Quad chip to perform a whole genome analysis of 592,532 single nucleotide polymorphisms (SNP), we found significant SNP genotype differences in the PARK2 gene between BRCA1 185delAG mutation carriers who developed gynecologic cancer (cases) compared to those who did not (controls). These SNPS created a haplotype structure that was present at four-times higher frequency in cases than controls (37% vs. 9%, p=0.0009). We hypothesized that PARK2, which has been shown to be mutated in other cancers and to have a tumor suppressive function, plays a role in the biology of BRCA1-associated gynecologic cancer development.
Experimental Procedures: To validate a PARK2 risk haplotype in an independent dataset, we isolated germline DNA from 85 BRCA1 185delAG mutation carriers and used TaqMan SNP Genotyping to genotype seven SNPs in PARK2. To determine whether a correlation exits between the PARK2 risk haplotype and PARK2 expression levels in tissue, we quantified PARK2 expression in normal ovaries and ovarian cancer tissue using quantitative real-time PCR (qPCR). To determine the rate of PARK2 mutations in 17 BRCA1-associated ovarian cancers, we used a touchdown PCR protocol to amplify and sequence each PARK2 exon. To identify exon deletions and duplications in the PARK2 gene, we utilized the multiplex ligation-dependent probe amplification (MLPA) technique.
Summary of Data: In an independent dataset of 85 BRCA1 185delAG mutation carriers, we found the PARK2 risk haplotype to be present in 35 (17%) of cases. The risk haplotype was present in a higher proportion of cancer cases than benign controls (6/12 or 50% vs. 29/73 or 8%), but this was not significant (p=0.54). We did not find a difference in PARK2 ovarian tissue expression levels in patients with and without the PARK2 risk haplotype. We sequenced the PARK2 gene and performed MPLA analysis from tumor DNA of 17 ovarian cancers from BRCA1 185delAG mutation carriers, but did not identify any deleterious PARK2 mutations or exon deletions and duplications.
Conclusions: We did not validate a PARK2 risk haplotype as a modifier of gynecologic cancer penetrance in BRCA1 185delAG mutation carriers. We did not find evidence for PARK2 inactivation in BRCA1-associated gynecologic tumors.
Citation Format: Christine Walsh, Hoorig Nassanian, Hasmik Agadjanian, Carl Miller, Sandra Orsulic, Beth Karlan. No association between PARK2 and BRCA1-associated gynecologic cancers [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1348.
Abstract POSTER-BIOL-1351: Molecular characterization of cyclin-dependent kinase 1 pathway in newly established epithelial ovarian cancer cell lines
Authors: Yang Wookyeom , Cho Hanbyoul , Sol Kim , Kim Jae-Hoon 
Published: August 2015

Abstract
Background: Epithelial ovarian cancer (EOC) is a heterogeneous gynecologic tumor. To better understand the biological pathways involved in the development of EOC, we performed mRNA expression profiling on newly established EOC cell lines.
Methods: Five newly established EOC cell lines were characterized by transcript profiling. Microarray analyses were validated using quantitative real-time PCR (RT-PCT) and immunoblotting. Furthermore, biological networks of the differentially expressed genes were predicted using the STRING database and literature review.
Results: A total of 239 genes represented by 24,957 probes were identified from microarray analysis, of which 98 and 141 genes are up- (&gt; 2 fold, p &lt; 0.05) or down-regulated (&lt; 3 fold, p &lt; 0.05), respectively, in EOC cell line compare to human ovarian surface epithelial cell lines. We identified a subset of EOC characterized by the numerous genes related to cell cycle and apoptosis, along with cyclin-dependent kinase 1 (CDK1). A total of 24 genes were validated by quantitative RT-PCR, and expressional reliabilities of 4 CDK1 pathway-related genes were confirmed by immunoblotting. Further biological network analysis revealed that the CDK1 pathway might be essential for EOC tumorigenesis.
Conclusions: These data reveal that the CDK1 pathway is important to EOC development and progression, providing new insight into the biology of EOC.
Citation Format: Wookyeom Yang, Hanbyoul Cho, Kim Sol, Jae-Hoon Kim. Molecular characterization of cyclin-dependent kinase 1 pathway in newly established epithelial ovarian cancer cell lines [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1351.
Abstract POSTER-BIOL-1352: Notch3 promotes anoikis resistance in ovarian cancer
Authors: Brown Caitlin W. , Brodsky Alexander S. , Freiman Richard N. 
Published: August 2015

Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. Recently, a number of genome-wide studies in ovarian cancer patient samples have postulated that the course of disease can influenced by the Notch3 signaling pathway. In one study, 11% of human tumor samples showed mutation or amplification of the Notch3 receptor alone. Subsequent papers have correlated Notch3 overexpression in human samples with shorter progression-free survival as well as overall survival. In vitro studies have shown Notch3 to be involved in apoptosis resistance and chemoresistance, as well as cell cycle alterations. Together, these human studies have implicated Notch3 expression and amplification with decreased outcomes in ovarian cancer patients.
To test the potential mechanism by which Notch3 over-expression promotes ovarian cancer, we examined several molecular and cellular functions of Notch3 in ovarian cancer cells. Decreasing the levels of Notch3 in ovarian cancer cells increases the susceptibility of these cells to apoptosis, which is consistent with previous studies. Using an effective siRNA-mediated knockdown of Notch3 combined with transfer to ultra-low attachment plates revealed a significant decrease in the ability of Notch3-knockdown IGROV-1 cells to remain viable in anchorage-independent conditions over 24 hours. Our data show that not only does Notch3 prevent apoptosis, but specifically promotes anoikis resistance. Further examining the mechanism underlying this novel finding revealed the positive roles of extracellular matrix proteins and FAK in promoting the anchorage-independent growth of IGROV-1 cells. Strikingly, mRNA and protein levels of col4α2 are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation can largely reverse the anoikis sensitivity. Reduction of col4α2 expression by siRNA induces cell death on its own and high Notch3 expression levels correlate with higher col4α2 expression in human ovarian tumor samples. Together, these studies have revealed that Notch3 promotes anoikis resistance through col4α2 expression and may partly explain its positive correlation with poor survival in ovarian cancer patients.
Citation Format: Caitlin W. Brown, Alexander S. Brodsky, Richard N. Freiman. Notch3 promotes anoikis resistance in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1352.
Abstract POSTER-CTRL-1209: Ovarian cancer disparities in a high volume academic medical center
Authors: Hunt Hayley , Rodriguez Noah , Oda Keiji , Wagner Robert J. , Swensen Ron E. 
Published: August 2015

Abstract
Objective: To identify disparities in care and survival in ovarian cancer patients treated at a high volume academic center.
Methods: A review of epithelial ovarian cancer cases treated between 01/01/97 and 12/31/07 was conducted. Demographic, clinico-pathologic, insurance carrier, and treatment data were collected. Insurance carrier was categorized into three groups: Commercial, Medicare, and Medicaid. ANOVA or Kruskal-Wallis tests were utilized for continuous variables and chi-square or Fisher’s exact tests for categorical variables. Univariable Cox proportional hazards model was used to estimate hazard ratios for demographic and pathologic variables identified in association with survival. Multivariable Cox regression models were fitted with insurance status as the main exposure. Kaplan-Meier survival curves were generated for race, income, and insurance and compared utilizing log-rank tests.
Results: 279 epithelial ovarian cancer cases were identified out of 460 total ovarian cancer cases. 199 (71%) were White and 80 (29%) were non-White. 159 (57%) had commercial insurance followed by 71 (25%) and 49 (18%) with Medicaid and Medicare, respectively. 166 (60%) of the study group had less than $45,000 as an annual median income. 219 (78%) patients underwent primary debulking surgery. Of the three insurance categories, women with commercial insurance had a survival advantage (p= 0.002). Medicaid was associated with worse survival after adjusting for grade, stage, residual disease, and chemotherapy (p= 0.04). Survival rates in advanced stage disease were similar across the 3 insurance carriers.
Conclusions: Ovarian cancer survival disparities persist at a high volume center but are largely eliminated in advanced stage.
Citation Format: Hayley Hunt, MD, Noah Rodriguez, MD, Keiji Oda, MPH, Robert J. Wagner, MD, Ron E. Swensen, MD. Ovarian cancer disparities in a high volume academic medical center [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1209.
Abstract POSTER-CTRL-1213: Whole exome and targeted resequencing, of population based ovarian cancer cases and controls, identifies susceptibility genes for ovarian cancer
Authors: Ramus Susan J. , Song Honglin , Dicks Ed , Intermaggio Maria , Hayward Jane , Tyrer Jonathan P. , Gronwald Jacek , Kjær Susanne Krüger , Wittemore Alice , Karlan Beth , Odunsi Kunle , Menon Usha , Bowtell David D. , Goode Ellen L. , Pharoah Paul D.P. , Gayther Simon A. 
Published: August 2015

Abstract
The known genetic variance for epithelial ovarian cancer (EOC) accounts for less than half the familial risks of the disease. BRCA1 and BRCA2 are the major high-penetrance EOC susceptibility genes. More recently genes that interact with BRCA1 and BRCA2 in the same biological pathways, but conferring more moderate penetrance (e.g. RAD51C, RAD51D) have also been identified. Mutations in these genes result in defects in homologous recombination and double strand break repair (HR/DSB). We hypothesized that other genes operating in these and other DNA repair pathways may also confer EOC susceptibility. Whole exome sequencing data, available from more than 400 high-grade serous ovarian cancers, were used to identify 24 candidate genes harboring germline truncating mutations in at least 2 cases, followed by replication analysis using targeted resequencing in ~3,000 cases and 3,000 controls. Subjects were also sequenced for the known susceptibility genes listed above. The data confirmed the previously reported contributions of BRCA1, BRCA2, RAD51C and RAD51D to EOC. In addition, we identified BRIP1, and FANCM as candidate EOC susceptibility genes. Surprisingly, for several genes we found truncating mutations were equally prevalent in cases as they were in controls. These mutations may still represent rare low-penetrance susceptibility alleles for EOC, which we are too limited in sample size and power to confirm; or more likely, it indicates that cells can tolerate heterozygous loss-of-function mutations in apparently critical DNA repair genes without any impact on neoplastic development. These findings may have implications for risk prediction and prevention strategies for EOC and possibly for the identification of novel therapeutic targets.
Citation Format: Susan J. Ramus, Honglin Song, Ed Dicks, Maria Intermaggio, Jane Hayward, Jonathan P. Tyrer, Jacek Gronwald, Susanne Krüger Kjær, Alice Wittemore, Beth Karlan, Kunle Odunsi, Usha Menon, David D. Bowtell, Ellen L. Goode, Paul D.P. Pharoah, Simon A. Gayther. Whole exome and targeted resequencing, of population based ovarian cancer cases and controls, identifies susceptibility genes for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1213.
Abstract POSTER-TECH-1101: Characterization of genomic landscapes of BRCA1 and BRCA2 implicated ovarian cancer specimens from a founder french canadian population
Authors: AlShehri Eman , Belanger Moria , Arcand Suzanna , Oros Kathleen Klein , Greenwood Celia , Tonin Patricia N. 
Published: August 2015

Abstract
Although molecular genetic profiling of ovarian cancers harboring germline BRCA1/BRCA2 mutations suggest that pathways in common with sporadic cases are involved in the pathogenesis of the disease, overall survival differs between BRCA1, BRCA2 and sporadic disease. To further dissect molecular pathways involved, which could account for differences in pathogenesis of the disease, we have investigated genomic landscapes in the BRCA1 and BRCA2 mutated ovarian cancers. Chromosomal anomalies were assessed in 28 specimens with BRCA1 (n=15), BRCA2 (n=12) or BRCA1 and BRCA2 (n=1) mutations using high-density Illumina SNP arrays. The majority (22/28) are serous adenocarcinomas while the remaining samples were either endometroid (2/28) or mixed adenocarcinomas (4/28). The cases harbor BRCA1/BRCA2 mutations from a French Canadian population, which exhibit strong founder effects. Allelic imbalance, copy number differences, intrachromosomal breaks and homozygous deletions were inferred visually using the Genome Viewer module of the BeadStudio software followed by ASCAT analysis. A statistical analysis was used to directly compare genotypes of BRCA1 versus BRCA2 positive samples. TP53 gene mutation status was also assessed. All samples were found to harbor a somatic TP53 mutation comprised of missense (19/28), nonsense (2/28), frame-shift (4/28) and (3/28) splice mutations. The results were compared to independently derived data generated previously from our group, which was largely comprised of sporadic cases (Wojnarowicz et al 2012), and to the genomic data from the Cancer Genome Atlas project (TCGA). The genomic landscapes of BRCA1 and BRCA2 mutated cancers overlap those reported in previous studies. However, there were significant differences in the genomic landscapes involving chromosome 6q between BRCA1 and BRCA2 mutation-positive cancers. This genomic distinction between BRCA1 and BRCA2 ovarian cancer samples may point to a region containing genes important in the etiology or progression of hereditary cancer.
Citation Format: Eman AlShehri, Moria Belanger, Suzanna Arcand, Kathleen Klein Oros, Celia Greenwood, Patricia N. Tonin. Characterization of genomic landscapes of BRCA1 and BRCA2 implicated ovarian cancer specimens from a founder french canadian population [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1101.