bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1984: Activated BMP signalling modulates multicellular spheroid formation and reattachment of ascites-derived human epithelial ovarian cancer cells in an in vitro model of metastasis
Authors: Peart Teresa M. , Bertrand Monique , Prefontaine Michel , Sugimoto Akira , DiMattia Gabriel , Shepherd Trevor 
Published: August 2014

Abstract
Epithelial ovarian cancer (EOC) comprises close to 90% of ovarian tumours, and over 75% of cases are not discovered until advanced metastatic stages. Therefore, there remains a critical need to identify the mechanisms controlling late-stage spread of disease and develop more effective treatment regimes. EOC cells have the ability to form multicellular aggregates in malignant ascites which dramatically alters cell signalling, survival, and metastatic potential. Primary human EOC cells derived from patient ascites secrete and are responsive to bone morphogenetic proteins (e.g. BMP2 and BMP4). BMPs can function in an autocrine fashion to enhance the malignant characteristics displayed by EOC cells in adherent monolayer culture. Herein, we demonstrate that EOC cells with enhanced BMP signalling form smaller, more loosely-aggregated spheroids than control cells when grown in suspension culture. Upon reattachment to standard tissue culture plastic, EOC spheroids readily attach and cells disperse from the attached spheroid; EOC spheroids with enhanced BMP signalling have an increased cell dispersion rate when compared with controls. Activated BMP signalling in EOC spheroids induces Smad1/5/8 phosphorylation, increases ID1 and ID3 proto-oncogene expression, and promotes epithelial-mesenchymal transition as evidenced by increased Snail and Slug and reduced E-cadherin markers. To identify additional target genes mediating the phenotypic changes in EOC spheroids due to activated BMP signalling, we performed genome-wide expression analyses using Affymetrix arrays. From this study, 102 genes were significantly upregulated and 52 downregulated in primary human EOC cells and spheroids with enhanced BMP signalling. A number of these genes have been previously identified as BMP targets or members of the BMP signalling pathway, several of which are involved in negative feedback regulation (e.g. noggin, Smad6 and Smad7), as well as several genes encoding proteins associated with cellular adhesion. In addition, using the online Connectivity Map resource (www.broadinstitute.org/cmap), we revealed that the PI3K-Akt-mTOR pathway may be impacted by an activated BMP pathway in EOC cells. Indeed, BMP signalling induces phosphorylation of Akt in both adherent primary human EOC cells and multicellular spheroids. Thus, we are currently investigating whether the PI3K-Akt pathway and the targets identified by microarray analysis are required for the BMP signalling effects on EOC spheroid formation and reattachment.
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 1984. doi:10.1158/1538-7445.AM2011-1984
Abstract 1988: A bi-directional feedback loop between Wnt and ERK is important in maintaining the proliferative phenotype of normal human urothelial cells
Authors: Kirkwood Lisa A. , Georgopoulos Nikolaos T. , Southgate Jennifer 
Published: August 2014

Abstract
Introduction: The urothelial lining of the bladder is ordinarily mitotically quiescent, but can rapidly regenerate in response to injury. This regenerative capacity is thought to be important in restoring urinary barrier function and offers a primary target for deregulation in cancer. Previous work in our laboratory has implicated autocrine EGFR activation in this process, but other regulatory pathways may be involved.
Wnt signalling has been shown to be important in the renewal of a number of adult epithelial tissues, but to date, no conclusive evidence for a role for Wnt in urothelial regeneration has been demonstrated. In the absence of Wnt ligand, β-catenin is sequestered via the destruction complex. Activation of the canonical Wnt pathway by ligand, inactivates the destruction complex, allowing β-catenin to translocate to the nucleus and drive proliferation.
The aim of this study was to assess whether Wnt signaling was functional in normal human urothelial (NHU) cells, and to analyze the effects of Wnt and downstream EGFR signaling on proliferation.
Materials and Methods: NHU cells were grown as finite lifespan cell lines in proliferating cultures. Destruction complex antagonists were used to activate the Wnt pathway. Proliferation assays, immunofluorescence labeling and TOPFLASH luciferase reporter assays were used to assess NHU cell responses. Pathway crosstalk was analyzed using shRNA targeted to β-catenin, as well as antagonists of the EGFR signaling pathways.
Results: Pharmacological inhibition of the destruction complex or activation of the Wnt pathway with exogenous Wnt ligand led to nuclear accumulation of β-catenin and an increase in TCF/LEF transcription factor activity. These effects were only apparent when autocrine EGFR signaling was blocked. Knockdown of β-catenin led to significant changes in p-ERK and p-AKT downstream signaling.
Conclusion: Wnt signaling can be activated in NHU cells, verifying the presence of a functional pathway. Activation of the pathway is however masked by EGFR signaling, indicating pathway crosstalk. The effect of β-catenin knockdown on p-ERK and p-AKT indicates a bi-directional positive feedback loop between the Wnt and EGFR signaling cascades in NHU cells. This study identifies the Wnt signaling pathway as an important signaling cascade in regulating the regenerative phenotype of NHU cells and indicates at least two pathways that may be arrogated by urothelial cells during neoplastic transformation.
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 1988. doi:10.1158/1538-7445.AM2011-1988
Abstract 1996: Chronic arsenic exposure and changes in global levels of histone modifications in a human population in Bangladesh
Authors: Chervona Yana , Arita Adriana , Wu Fen , Sun Hong , Kiok Kathrine , Kluz Thomas , Tseng Hsiang-Chi , Zavadil Jiri , Leroy Gary , Gamble Mary , Costa Max 
Published: August 2014

Abstract
Arsenic and arsenic compounds have been classified as group 1 human carcinogens by IARC. Naturally occurring inorganic arsenic, in particular, has been implicated in the development of human skin, lung, and bladder cancers and has also been associated with the development of liver and prostate cancers. However, despite being a formidable carcinogen, arsenic is a poor mutagen and it has been suggested that arsenic-induced carcinogenesis maybe governed by epigenetic mechanisms. We have detected differences in the levels of several histone epigenetic marks, such as H3K9acetylation, H3K9dimethylation and H3K27trimethylation in human peripheral mononuclear cell collected from individuals exposed to varying levels of inorganic arsenic in their drinking water. The changes in the global levels of these epigenetic marks were primarily measured using a novel ELISA method, while changes of arsenic-induced histone modifications in peripheral blood lymphocytes treated in vitro have also been examined via Mass Spectrometry and Western Blotting. Furthermore, we have also found a profound increase in the expression of histone genes after in vitro treatment of peripheral blood lymphocytes with sodium arsenite and will be examining this finding further. To the best of our knowledge, this study is the first in its class to measure arsenic-induced epigenetic modifications in humans and how they relate to changes in gene expression in a human population.
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 1996. doi:10.1158/1538-7445.AM2011-1996
Abstract 1998: Aberrant methylation of BRCA/HR pathway genes and response to platinum-taxane therapy in ovarian cancer
Authors: Maradeo Marie E. , Morgan Mark A. , Burger Robert A. , Cairns Paul 
Published: August 2014

Abstract
Women diagnosed with ovarian cancer generally receive debulking surgery in combination with platinum-taxane based chemotherapy. While this treatment is currently the most effective, women diagnosed with Stage III and IV ovarian cancer have a less than a 20% five-year survival rate. Ovarian tumorigenesis is a multi-step process that results from the sequential accumulation, and interplay, of genetic and epigenetic mutations in critical genes. It is likely that such mutations underlie the different responses to therapy.
There are several reports that demonstrate that women with germline mutations in BRCA genes and inherited ovarian cancer have a favorable survival as compared to women with sporadic ovarian cancer that is matched for pathological stage. The BRCA1 and BRCA2 genes function to repair DNA damage and maintain genetic stability through the homologous recombination (HR) repair pathway. Much of the superior survival is likely due to hypersensitivity to platinum-containing chemotherapy that in turn is due to incompetent DNA repair of platinum DNA adducts due to faulty HR repair of double stranded DNA breaks (DSBs).
It is hypothesized that sporadic ovarian tumors, which constitute the vast majority of ovarian cancer, with epigenetic suppression of BRCA or BRCA-associated proteins, e.g. aberrant promoter hypermethylation of BRCA1, will be relatively hypersensitive to platinum as compared to ovarian tumors with an intact BRCA/HR pathway. To answer this important question, we have used bisulfite sequencing and quantitative methylation specific PCR to examine the incidence of epigenetic impairment of BRCA/HR pathway genes, including BRCA1, PALB2 and other genes, in primary human epithelial ovarian cancer and, using these results, then examined the relative frequency of BRCA/HR pathway impairment in sporadic ovarian tumors separated into cohorts by time to progression after platinum-taxane therapy and other measures of outcome.
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 1998. doi:10.1158/1538-7445.AM2011-1998
Abstract 200: Identification of proteins involved in c-Myc induced mammary epithelia apoptosis in 3D culture system
Authors: Huang Ling , Tai Elizabeth , Muthuswamy Senthil K. 
Published: August 2014

Abstract
Identification of proteins involved in c-Myc induced mammary epithelia apoptosis in 3D culture system We have previously discovered that depletion of a cell polarity gene Scribble in mammary epithelial cells disrupted cell polarity, apoptosis and morphogenesis in three dimensional cell culture as well as inducing dysplasia that progressed into tumor in mice. Loss of Scribble also inhibited c-Myc induced apoptosis to cause cell transformation in vitro and tumor formation in vivo. Scribble mutant with deficiency in membrane localization resulted in similar phenotypes. These results suggest that Scribble is a tumor suppressor in mammary gland epithelial cells and its functions depends on correct cellular localization. Furthermore, Scribble is required to inhibit Myc-induced tumorigenesis by blocking Myc-induced apoptosis. I am interested in identifying proteins that are involved in Scribble dependent apoptosis as well as discovering other polarity proteins that cooperate with c-Myc for mammary tumor progression. To address the two questions, I use MCF10A three dimensional culture system and RNAi technology to screen proteins participating in apoptosis during c-Myc induced mammary epithelial cell transformation. We will report a screen to identify proteins that are involved in c-Myc induced mammary epithelial cell apoptosis in 3D culture, using a lentiviral shRNA library.
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 200. doi:10.1158/1538-7445.AM2011-200
Abstract 2000: Investigation of the molecular events associated with gene resilencing following withdrawal of epigenetic therapies
Authors: Hesson Luke B. , Patil Vibha , Sloane Mathew , Ward Robyn L. 
Published: August 2014

Abstract
Epigenetic therapies are a potential new class of anticancer medication for the treatment of solid tumors as well as haematological malignancies. These therapies reverse changes to DNA methylation and histone modifications allowing re-expression of epigenetically inactivated genes. However, upon drug withdrawal reactivated genes undergo re-silencing. This study investigates the mechanism of gene re-silencing following withdrawal of epigenetic therapies, in an effort to identify strategies which deliver a permanent re-expression of epigenetically inactivated genes. Using the mismatch repair gene MLH1 as a model we investigated the molecular events associated with the re-silencing process in the colorectal cancer cell line RKO. These cells lack MLH1 expression due to biallelic promoter DNA hypermethylation. We treated RKO cells for 72hrs with a combination of 2.56µM 5-aza-2’deoxycytidine (a DNA methyltransferase (DNMT) inhibitor) and 19nM Trichostatin A (a histone deacetylase (HDAC) inhibitor). We observed MLH1 re-expression by quantitative RT-PCR, concomitant with de-methylation at the MLH1 promoter as determined by bisulphite sequencing. Methylation at the MLH1 promoter decreased from 90.9% in mock-treated cells to 74.7, 61.7, 62.4 and 65.9% at 0, 3, 5 and 7 days after drug withdrawal, respectively. We observed a reproducible re-silencing of MLH1 gene expression, which began three days after drug withdrawal and was complete by 120 days. We further demonstrate the recruitment of a nucleosome, located immediately upstream of the transcription start site, prior to the re-silencing of MLH1 expression that remained high whilst MLH1 transcript levels decreased. We propose that the recruitment of promoter nucleosomes precedes a reduction in transcriptional output and the re-methylation of promoter DNA. Ongoing work aims to dissect the re-silencing process further by investigating the dynamics of RNApolII occupancy and histone modifications at the MLH1 promoter. This study provides important information on the molecular events associated with gene re-silencing by addressing the temporal relationship between changes to gene expression, nucleosomal occupancy and DNA methylation.
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 2000. doi:10.1158/1538-7445.AM2011-2000
Abstract 393: The chemokine receptor, CXCR2/IL8RB, contributes to the survival of pancreatic adenocarcinoma, and may play a role in stroma-tumor communication
Authors: Ustach Carolyn V. , Watanabe Aprill , Aziz Meraj , Diep Caroline , Hostetter Galen , Michael Demeure , Han Haiyong , Von Hoff Daniel D. 
Published: August 2014

Abstract
The failure of most chemotherapeutic agents to treat pancreatic cancer could be related to poor delivery of drug due to the physical barrier of dense fibrosis surrounding the tumor. Targeting and attenuating the fibrotic stroma may result in better access of drug to tumor. Our current studies show that CXCR2/IL8RB is over-expressed in the surrounding stroma of pancreatic ductal adenocarcinoma tumors. CXCR2/IL8RB and its ligands are well known to be involved in fibrosis, and recently published papers suggest a role for CXCR2 in tumor proliferation, as well. Therefore, CXCR2 is a good target for pancreatic cancer therapy, because it has the potential to target both the stroma surrounding the tumor, as well as the tumor itself. When comparing matched samples of patient tumor and adjacent normal tissue, the mean IHC score of stroma surrounding normal pancreatic ducts is 0.61 (95% CI 0.38-0.84), while the mean IHC score of stroma surrounding ductal adenocarcinoma is 1.6 (95% CI: 1.3-1.9; Mann-Whitney test p&lt;.0001; n=31). We previously reported that a CXCR2 ligand, CXCL5, was highly expressed in patient tumor samples, but not in the stroma. Interestingly, our present data shows CXCR2 is also expressed in tumor cells, therefore, CXCR2 may be involved in both autocrine and paracrine signaling inducing tumor proliferation, as well as induction of fibrosis in the stroma. Supporting CXCR2's role in pancreatic tumor proliferation, specific knockdown of CXCR2 expression by siRNA reduces cell growth by approximately 50%. Additionally, drug dose response curve experiments show pancreatic cancer cell lines which express CXCR2 are more sensitive to the CXCR2 antagonist, SB225002, than cells which do not express CXCR2. For example, the CXCR2 expressing cell line PANC-1 is approximately 7 times more sensitive to SB225002 than the CXCR2 negative cell line BxPC-3 (0.12uM vs. 0.88uM in IC50). We are currently assessing the mechanism of death induced by CXCR2 inhibition in the cancer cells. CXCR2's role in tumor cell proliferation, as well as its over-expression in the stroma surrounding tumors, make it a good target for both weakening the protective stroma surrounding the tumor, and reducing tumor cell survival.
This work was supported by NIH P01 Grant CA109552.
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 393. doi:10.1158/1538-7445.AM2011-393
Abstract 3933: Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling
Authors: Wagle Nikhil , Emery Caroline , Berger Michael F. , Davis Matthew J. , Sawyer Allison , Pochanard Panisa , Kehoe Sarah M. , Johannessen Cory M. , Macconaill Laura E. , Hahn William C. , Meyerson Matthew , Garraway Levi A. 
Published: August 2014

Abstract
Although targeted anticancer agents often result in dramatic responses, tumors invariably become resistant to these agents. A detailed understanding of the mechanisms by which tumors acquire resistance to such inhibitors should speed the development of more durable treatment strategies. The promise of RAF inhibition in metastatic melanoma is exemplary in this regard. Mutations in the BRAF oncogene have been detected in more than 50% of metastatic melanomas, and inhibition of mutant BRAF has shown high response rates in early clinical trials of patients with melanoma. However, resistance to RAF inhibition invariably develops. Mechanisms of de novo and acquired resistance to RAF inhibition remain poorly understood. Moreover, the clinical application of genomic approaches that might be capable of diagnosing salient resistance mechanisms remains underdeveloped.
Here, we describe an approach to characterize genetic mechanisms of resistance through systematic tumor mutation profiling. We performed massively parallel sequencing of 138 cancer genes in a tumor specimen from a melanoma patient who developed resistance to PLX4032 after a dramatic initial response. The resulting profile identified a novel mutation in the downstream kinase MEK1 that was absent in the corresponding pre-treatment tumor. This MEK1 mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Our results provide an instructive framework both for assessing mechanisms of acquired resistance to kinase inhibition and deploying new technologies for elaboration of resistance mechanisms in a manner that may accelerate personalized cancer medicine.
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 3933. doi:10.1158/1538-7445.AM2011-3933
Abstract 3937: Global methylation patterns, genome copy number alterations and expression analysis distinguish two distinct subclasses of hepatocellular carcinoma
Authors: Revill Kate , Tim Wang , GInther Charles L. , Anderson Lee , Aleshin Alexey , Busuttil Ronald W. , Powers Scott , Finn Richard S. 
Published: August 2014

Abstract
Background: Hepatocellular carcinoma (HCC) is a devastating disease ranking as the third most frequent cause of cancer deaths worldwide. In the US, the incidence of HCC tripled between 1975 and 2005 and at present day survival rates are as low as 20% due to limited treatment options. Future therapeutic advances rely on a greater understanding of the full range of genetic and epigenetic defects displayed by this cancer. Recent advances in whole genome methylation profiling have allowed us to investigate these alterations in a cohort of HCC and normal liver samples.
Methods: Using the Illumina Infinium platform, we analyzed the methylation patterns in over 50 human HCC and normal liver samples obtained from surgical resection and transplant specimens. We also investigated the expression and gene copy number (CGH) status on the same cohort using the Agilent platform.
Findings: We have been able to identify two very distinct groups of HCC based on their methylation status. In each class of tumors, there are both hypo- and hypermethylated genes relative to normal liver. Several of these tumor-specific alterations have been validated by pyrosequencing. In one class of tumors, many genes that are normally repressed by polycomb group proteins in stem cells are hypermethylated, consistent with the tumor cell of origin being a progenitor stem cell. The other class of tumors does not show this association and are likely to originate from a different cell of origin. Intriguingly, these two classes also correspond to distinct groups based on both DNA copy number analysis and expression analysis.
Conclusion: Combining these three independent methods of global analysis; expression profiling, epigenome analysis and CGH data, we have identified a robust new classification scheme for HCC. This approach should provide insight for future therapeutic advances.
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 3937. doi:10.1158/1538-7445.AM2011-3937