bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 162: DNA methylome in familial breast cancer identifies distinct profiles defined by mutation status
Authors: Flanagan James , Cocciardi Sibylle , Waddell Nic , Johnstone Cameron , Henderson Stephen , Simpson Peter , da Silva kConFab, Leonard , Khanna Kumkum , Lakhani Sunil , Boshoff Chris , Chenevix-Trench Georgia 
Published: February 2011

Abstract
It is now understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA methylation profiling on frozen, familial breast cancers (n=33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2 and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2-amplified and normal-like). We used methylated DNA immunoprecipitation (meDIP) on Affymetrix promoter chips to interrogate methylation profiles across 25,500 distinct transcripts, and performed technical validation of multiple loci with Epityper. Using a support vector machine classification algorithm, we demonstrated that genome-wide methylation profiles predicted tumor mutation status with estimated error rates of 19% (BRCA1), 31% (BRCA2) and 36% (BRCAx), but did not accurately predict the intrinsic subtypes defined by gene expression with error rates of 43% (basal) and 54% (luminal A). Furthermore, using unsupervised hierarchical clustering we identified a distinct subgroup of BRCAx tumors defined by methylation profiles. We then validated these findings in the original 33 tumours and in an independent set of 47 formalin-fixed, paraffin embedded BRCA1 (n=14), BRCA2 (n=13) and BRCAx (n=20) tumours by Pyrosequencing. “Finally, gene expression profiling and SNP CGH array previously performed on the same samples allowed full integration of methylation, gene expression and copy number data sets. This integrated analysis revealed frequent hypermethylation of genes that also displayed loss of heterozygosity (LOH) compared to the tumors that were diploid for that gene. We also observed frequent hypermethylation of genes that show copy number gains compared to diploid tumors providing a potential mechanism for expression dosage compensation. Together these data show that methylation profiles for familial breast cancers are defined by the mutation status and distinct from the intrinsic subtypes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 162.
Abstract 1625: Discovery of a breast cancer targeting peptide with anti-tumor activity
Authors: Proneth Bettina , Driessen Wouter H. , Hajitou Amin , Staquicini Fernanda I. , Arap Wadih , Pasqualini Renata 
Published: February 2011

Abstract
The American Cancer Society estimates 192,370 women will be diagnosed with breast cancer in the United States in 2009, and approximately 40,170 will die of this disease. Towards identifying new ligand-directed therapies for breast cancer, we have developed an in vivo screening method, where peptides that home specifically to the vascular component of tissues are selected after intravenous administration of an engineered combinatorial peptide phage library. We have used this technology for the identification of a new breast cancer targeting peptide and its receptor in a mouse model of highly aggressive and vascularized breast cancer.
A random phage library displaying the cyclic sequence CX7C (X = any of the 20 natural amino acids) was injected intravenously in tumor-bearing mice after which phage was recovered from the tumor-tissue by bacterial infection and re-injected for a subsequent round of biopanning. After sequencing of the recovered phage from round 2 and 3 several candidate peptides were identified. One breast cancer targeting peptide (BCTP) was recovered from all tumors with the highest frequency. This peptide showed marked tumor homing as verified by immunohistochemistry (IHC). We used peptide affinity chromatography and tandem mass spectrometry (MS/MS) to identify the target receptor of BCTP. Strikingly, this newly discovered receptor plays an as yet unrecognized role in the pathology of breast cancer. BCPT exhibited strong binding to its receptor as verified by ELISA. To investigate if the BCTP receptor is a relevant candidate drug target in breast cancer, we obtained biopsy samples of breast cancer patients prior to chemotherapy. Strong immunoreactivity of the BCTP receptor was observed in the paraffin embedded tissue sections. Next, mammary tumor-bearing mice were injected twice per week with BCTP, control peptide or saline, systemically. BCTP treated mice demonstrated a marked decrease in tumor size of treated mice, compared to mice injected with PBS alone.
We have identified, characterized and validated the peptide BCTP, specifically homing to highly aggressive, vascularized breast tumors. In addition to its tumor targeting capabilities this peptide possesses anti-tumor function in itself, inhibiting tumor growth and progression in tumor-bearing mice. More importantly, the target receptor expression has been verified in human biopsy samples of breast cancer, indicating that this protein might be a promising new drug target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1625.
Abstract 1628: Tumor cell specific inhibition of oncogenic Wnt signaling
Authors: Takigawa Yutaka , Love Damon K. , Brown Anthony M. C. 
Published: February 2011

Abstract
Aberrant activation of the Wnt/β-catenin pathway is one of the most frequent signaling abnormalities known in human cancer and contributes to both tumor initiation and tumor maintenance. In normal tissues, however, the Wnt/β-catenin pathway plays widespread and important roles in the regulation of stem cell behavior, differentiation, and homeostasis. Consequently, a challenge in developing strategies for antagonizing Wnt signaling in cancer will be to minimize harmful side-effects on normal tissues. In many human cancers the canonical Wnt pathway is activated by single base missense mutations in β-catenin located near N-terminal phosphorylation sites that control the protein's stability. These mutant forms of β-catenin represent targets that are unique to cancer cells. We have screened RNAi reagents designed specifically to target individual mutant β-catenin sequences found in cancer cells while having minimal impact on wild-type β-catenin. We have used colorectal and hepatoma cell lines with defined β-catenin mutations for initial evaluation of the efficacy and specificity of knock-down, in conjunction with signaling assays based on nuclear accumulation of β-catenin and TCF-responsive reporter assays. We find that mutation-specific siRNA or shRNA reagents can be identified that substantially reduce β-catenin levels in cancer cells bearing the respective mutation, but have little or no effect on cells that are wild-type for β-catenin or which carry a different mutation. We also observe mutation-specific inhibitory effects on cell growth. These results provide encouragement for developing this strategy as a means of silencing oncogenic mutations in cancer while causing only minimal collateral damage to normal tissues.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1628.
Abstract 1629: Restoration of the wild type function to mutant p53 by chemopreventive agent phenethyl isothiocyanate
Authors: Wang Xiantao , Govind Sudha , Wu Jessie Yu-Chieh , Tomita York , Mi Lixin , Di Pasqua Anthony J. , Chung Fung-Lung 
Published: February 2011

Abstract
p53 mutations occur in more than 50% of all human tumor. Mutant p53 is incapable of activating downstream target genes necessary for cell cycle arrest and apoptosis. Phenethyl isothiocyanate (PEITC), a cruciferous vegetable-derived compound, has been shown to possess anti-cancer property by causing cell growth arrest or apoptosis in tumor cell lines and animal models. Recently, we have found that PEITC can selectively reduce mutant p53, but not wild type protein levels in a variety of tumor cell lines. Here, we demonstrate that PEITC can increase sequence specific DNA binding of p53 in NSCLC H596 cells expressing mutant p53 and induce the expression of p53-dependent target proteins, such as p21 and Noxa. Similar effects were observed in human glioblastoma T98G cells which also express mutant p53. H596 cells incubated with sulforaphane (SFN), another widely studied ITC compound with much weaker cytotoxicity, showed no increased specific DNA binding of p53. In addition, PEITC induced p53-responsive p21 and Noxa promoter luciferase activity. Blocking mutant p53 protein expression with shRNA in T98G cells entirely prevented p21 protein induction triggered by PEITC. Immunoprecipitation studies with conformation-specific p53 antibodies (Pab1620 and Pab240) show that treatment with PEITC alters mutant p53 to wild type conformation in H596 cells. Currently, we are investigating the significance of function restoration to mutant p53 by phenethyl isothiocyanate in the regulation of apoptosis by PEITC or other conventional chemotherapeutic drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1629.
Abstract 1633: The sphingosine kinase inhibitor SKI-II blocks survival and MAPK signaling in human breast cancer in vitro
Authors: White Martin D. , Antoon James W. , Meacham William D. , Slaughter Evelyn M. , Burow Matthew E. , Beckman Barbara S. 
Published: February 2011

Abstract
Endocrine resistance is a major contributor to treatment failure in breast cancer. A close examination of the signaling mechanisms by which cells may impart their resistance presents an attractive strategy for the development of viable treatment options. Sphingosine kinase (SK), and its product, sphingosine-1-phosphate (S1P), have been increasingly implicated in many disease states and SK/S1P signaling is a known regulator of apoptosis and cell survival. Furthermore, inhibition of sphingosine kinase has been shown to be anti-proliferative as well as apoptotic in a multitude of human cancer cell lines. In this study, we investigated the biological activity of the sphingosine kinase inhibitor, SKI-II (4-[[4-(4-Chlorophenyl)-2-thiazolyl]amino]phenol) and its ability to disrupt cell signaling in estrogen-dependent and endocrine-resistant breast cancer. SKI-II blocked both viability and survival at low micromolar IC50 concentrations in endocrine therapy-resistant MDA-MB-231, MDA-MB-468 and MDA-MB-361 cells in addition to endocrine therapy-sensitive MCF-7 breast cancer lines. Additionally, treatment with SKI-II significantly (p&lt;0.05) decreased proliferation, as seen in Ki-67 immunostaining. The potent biological activity of this inhibitor led us to characterize the precise molecular mechanisms in which SKI-II imparts its effects. Sphingosine kinase is known to affect various signaling cascades, and its effect on the MAPK and PI3K/Akt pathways are cell line dependent. Growth factor signals such as MAPK can cross-talk with estrogen receptor and confer hormone therapy resistance. Therefore, we chose to investigate several signaling cascades to determine if SK inhibition mediates its effect through disruption of signaling. SKI-II diminished phosphorylation of ERK1/2 in both a time-dependent and dose-dependent manner. Treatment with SKI-II also inhibited phosphorylation of p38/MAPK at similar concentrations. This blockade of MAPK signaling may contribute to SKI-II's dual anti-cancer effect, which can target ER activation in an estrogen-dependent and an estrogen-independent manner. Targeting the production of sphingosine-1-phosphate through pharmacological inhibition presents a potentially useful method to reset the cell signaling aberrations -which lead to endocrine resistance, and may contribute to overall greater efficacy of current therapeutic interventions by re-sensitizing cells to endocrine therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1633.
Abstract 1635: Combination of the HDAC inhibitor romidepsin with the MEK inhibitor U0126 results in synergistic plasma cell apoptosis
Authors: Gu Yanyan , Kaufman Jonathan , Boise Lawrence H. , Lonial Sagar 
Published: February 2011

Abstract
Histone deacetylase inhibitors such as vorinostat and panobinostat have been tested as single agents in patients with relapsed myeloma with nominal activity. Yet, when combined with the proteasome inhibitor bortezomib, clinical and laboratory evidence of synergy has been observed. We sought to evaluate the individual signaling effects of the HDACi romidepsin, with the intent of developing additional combinations that may lead to clues of mechanism of action on human myeloma cells.
Single agent studies demonstrated IC50 values for romidepsin alone of between 10 and 30nm, further experiments demonstrate that growth inhibition resulting from romidepsin exposure includes apoptosis and cell cycle arrest. Cell death is associated with increased caspase 3, 8, 9 and PARP cleavage. Cell cycle analysis indicates that romidepsin induces G0/G1 cell cycle arrest which is correlated with p21 upregulation. Cell signaling assessment demonstrates that romidepsin inhibits AKT phosphorylation. Surprisingly, romidepsin increases Erk phosphorylation with its resultant effects on cell growth, development and differentiation. Combining romidepsin with the MEK inhibitor U0126 suppresses MEK/ERK signaling, and synergistically enhances the antitumor effect of romidepsin (combination index value &lt;1). Annexin V staining demonstrates significant apoptosis following 18 hr of treatment with U0126 (5µM) and 10nM romidepsin. Western blot confirms the development of significantly increased procasepase and PARP cleavage, as well as substantial downregulation of Mcl-1, Bcl-xL. The combination can overcome the antiapoptotic effect of exogenous cytokines, such as IL-6 and IGF1 in vitro. Further studies evaluating the effect of bone marrow stromal cells will be presented in addition of data evaluating other potential targets for oncogene addiction that can be used for further novel combinations to gain more understanding of the biological context of this combination both in vitro and in vivo. This study will improve the design of effective clinical combination strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1635.
Abstract 1636: Anticancer drug-induced Jak2/Stat3 activation confers a survival advantage in lung cancer cells
Authors: Su Wen-Pin , Lo Ya-Chin , Lin Chien-Chung , Chen Helen H.W. , Lai Wu-Wei , Su Wu-Chou 
Published: February 2011

Abstract
Chemotherapy may trigger survival signaling in cancer cells and the cells may change the response to chemotherapy. Here we found chemotherapeutics-induced Jak2/Stat3 signaling activation, by which cancer cells escape from death in human lung cancer PC14PE6AS2 (AS2) and H157 cells with constitutively activated Stat3 protein. Cisplatin, paclitaxel and epirubicin are important agents in lung cancer treatment and they are reactive oxygen species (ROS)-producing agents. In AS2 and H157 cells, we found that during the paclitaxel treatment, early Jak2 activation occurred and then Stat3 tyrosine phosphorylation upregulated early. But Stat3 serine phosphorylation was not significantly increased. When AS2 and H157 cells were treated with cisplatin and epirubicin, the Jak2/Stat3 activation was also observed, which can be blocked by AG490. It is indicated that chemotherapy, such as paclitaxel, cisplatin and epirubicin, may activate Jak2/Stat3 pathway. In AS2 cells, chemotherapeutics generated ROS, and the chemotherapy-induced Jak2/Stat3 activation was only effectively inhibited by mitochondrial ROS scavengers as rotenone and antimycin. The similar finding was also observed in H157 cells. It is said that “mild” mitochondrial uncoupling provides a survival benefit in cancer cells. In AS2 and H157 cells, pretreatment with the mitochondrial uncoupler carbonylcyanide-4-trifluoromethoxy-phenylhydrazone (FCCP) inhibited paclitaxel-induced mitochondrial ROS generation, abolished paclitaxel-induced Stat3 activation in AS2 and H157 cells, and augmented paclitaxel-induced mitochondrial membrane potential decrease. Thereafter, we classified AS2 and H157 cells as “FCCP-responsive” or “less mitochondrial uncoupling” cancer cells. So that mitochondrial coupling-mediated oxidative stress modulated paclitaxel-induced Jak2/Stat3 activation in AS2 and H157 cells. Subsequently, Stat3 activation by chemotherapeutics enhanced survivin expression in AS2 and H157 cells. Pretreatment with AG490, FCCP and rotenone blocked paclitaxel-induced survivin expression in a dose-dependent manner. Pretreatment with FCCP and rotenone also made AS2 and H157 cells more sensitive to the drug. Conclusively, anti-cancer drugs-induced Jak2/Stat3 activation confers a survival advantage in lung cancer AS2 and H157 cells via mitochondrial-coupling mediated ROS generation. This is a new phenomenon of cellular response to chemotherapeutics, by which cancer cells escape from drug-induced death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1636.
Abstract 164: High-throughput epigenetic analysis of susceptibility loci identified by GWAS in pancreatic cancer
Authors: Lo Ken C. , Holster Heather , Jia Jinping , Parikh Hemang , Collins Irene , Brazas Robert , Selzer Rebecca , Amundadottir Laufey 
Published: February 2011

Abstract
Pancreatic cancer is a highly lethal cancer with few well established risk factors. A genome wide association study (GWAS) of pancreatic cancer (PanScan) is being conducted within the framework of the NCI-sponsored Cohort Consortium and the Pancreatic Cancer Case-Control Consortium (PANC4). Susceptibility loci discovered to date in PanScan are non-coding variants that lie in intronic or intergenic regions, suggesting that the underlying signals may function through regulatory mechanisms that influence gene expression or splicing. Alternatively, these may lie in unannotated transcripts and directly affect their function.
Epigenetic mechanisms, such as DNA methylation, can affect the regulation of gene expression and plays a critical role in the development of many human diseases including cancer. Powerful methods exist to analyze DNA methylation patterns in higher eukaryotes including methylated DNA immunoprecipitation (MeDIP), an affinity based approach to enrich methylated DNA regions from genomic DNA, which can be combined with microarrays to profile genomic DNA methylation patterns. We created a new semi-custom MeDIP-optimized array design based on our Human DNA Methylation 3×720K CpG Island Plus RefSeq Promoter array by tiling additional regions associated with pancreatic cancer that were identified in the PanScan study. To complement DNA methylation data a genome-wide transcriptome analysis was performed with RNA-sequencing (RNA-seq). Here we describe a comprehensive genome wide analysis of 8 pancreatic cancer cell lines to examine methylation patterns of Refseq promoters and annotated CpG islands as well as transcribed sequences.
One of the susceptibility loci from PanScan is in the vicinity of the ABO gene on Chr9q34 where four SNPs (rs505922, rs495828, rs657152 and rs630014) are associated with a significantly increased risk of pancreatic cancer. As a pilot study, DNA methylation patterns and expressed sequences in this locus were investigated in cell lines derived from pancreatic tumors and normal pancreatic tissues. Our genome wide DNA methylation and RNA-seq analysis aims at establishing a comprehensive catalog of epigenetic patterns in pancreatic cell lines that could provide plausibility for the association signal in the ABO gene and other GWAS regions and thereby, initiate the characterization of the molecular phenotype of the susceptibility alleles for pancreatic cancer risk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 164.
Abstract 1642: Preclinical studies of MK-8745: Correlation between Aurora-A inhibitor sensitivity and Aurora-A activator
Authors: Chowdhury Aparajita , Tsai Ming Y. 
Published: February 2011

Abstract
Selective small-molecule kinase inhibitors have emerged as an important class of anti-cancer agents, and have demonstrated encouraging clinical efficacy in several different malignancies. However, it has become clear that the clinical activity of these agents is typically limited to a subset of patients, indicating the need to develop a clear understanding of the various factors that influence clinical benefit. To date, most studies have identified cancer patients whose tumors have genetic alterations of the targeted kinase and have demonstrated their greatest clinical efficacy for the kinase inhibitors. However, recent drug discovery efforts are also being aimed at targeting kinases within oncogene-associated signaling pathways and the pathway-specific determinants of sensitivity. Aurora-kinase family members (Aurora kinases -A, B, C) have been implicated as key mitotic regulators essential for genomic stability. Aurora kinase A (AURKA) is highly expressed in multiple human cancers and has been shown to be a promising therapeutic target. In this study, we examined the effects of small molecule AURKA specific inhibitor MK-8745 on non-Hodgkin lymphoma (NHL) cells.
Our results indicate that MK-8745 treatment leads to cell cycle arrest at G2/M phase with accumulation of tetraploid DNA followed by mitotic catastrophe and cell death in five cell lines (Granta 519, Jeko1, JVM2, Z138C and Akata). More importantly, we found that the sensitivity of the cell to the AURKA inhibitor is strongly correlated to the expression level of AURKA activators. We found that siRNA knockdown of one of the AURKA activators TPX2 increased MK-8745 sensitivity in drug resistant cell lines (Granta 519), whereas overexpression of TPX2 in MK-8745 sensitive cell (Z138C) lines increased drug resistance. This differential drug-sensitivity is specific to MK-8745 since treatment with pan-Aurora inhibitor (VE465, inhibitor of Aurora-A, B and C) and another mitotic drug, Taxol, did not show a differential sensitivity in these cell lines. The AURKA phosphorylation was decreased by MK-8745 treatment with simultaneous reduction in endogenous AURKA substrate TPX2, Eg5 and TACC3 protein levels.
Our results suggest, beside p53, AURKA activators should be potential biomarkers for selecting subpopulations of patients for AURKA inhibitor treatment, while AURKA substrates can be the potential biomarkers for the effect of Aurora-A inhibitor treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1642.