bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4961: In human breast cancer cells thyroid hormone signaling overshadows estrogen signaling on SMP30 gene leading to induction of apoptosis
Authors: Mishra Sandip K. , Sar Pranati , Rath Bandita , Bhargava Dharmendra , Sengupta Debomita , Chaudhary Sanjib 
Published: August 2012

Abstract
Crosstalk between thyroid and estrogen hormones actions have been documented with regard to a variety physiological functions. Both of these hormones regulate transcription of target genes by binding to their nuclear receptors that interact with specific responsive elements (estrogen and thyroid hormone response elements, i.e. ERE and TRE, respectively. Recently, we have demonstrated that 3, 3′5 Triiodo L Thyronine (T3) can induce apoptosis in ER+ve highly metastatic breast cancer MCF-7 cells through downregulating Senescence marker protein-30 (SMP30) gene. SMP30 has also been reported to be downregulated by 17β-Estradiol (E2) in prostrate gland and mammary epithelial cells. Interestingly, thyroid receptors (TRs) and estrogen receptor (ER) share a common response element, so we hypothesised a possible competition between both the receptors in SMP30 promoter under different hormone responses. To prove this hypothesis, gel retardation and luciferase assays were conducted by taking hSMP30 promoter reporter construct validated our findings of the putative ERE site. Competition Chromatin immunoprecipitation assay (ChIP) showed prominent TRβ binding irrespective of thyroid and estrogen hormone treatment. As a result, there was a significant repression found in whole promoter activity in presence of T3 and also in presence of both E2 and T3 treatment. Although the SMP30 promoter activity was same in response to E2 and T3 but the functional consequences after downregulation of SMP30 in human breast cancer cells were different. Overall our studies indicate that estrogen signalling/downstream target molecules of E2 weren't affected by estrogen mediated SMP30 downregulation however, SMP30 downregulation by thyroid hormone synergized the effect of T3 by further inducing apoptosis in human breast cancer cells. Thyroid hormone induced apoptosis in human breast cancer cells was through activated p53 molecule.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4961. doi:1538-7445.AM2012-4961
Abstract 5071: The genomic landscape of pancreatic cancer: from discovery to patient care
Authors: Biankin Andrew V. , Grimmond Sean M. ,   Australian Pancreatic Cancer Genome Initiative
Published: August 2012

Abstract
Pancreatic Cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of &lt; 12 months even with maximal therapy, and a 5-year survival rate of &lt; 5%. The diversity of clinical outcomes and the molecular heterogeneity of histopathologically similar cancer types, incomplete knowledge of the genomic aberrations that drive carcinogenesis and the lack of therapeutics that specifically target most known genomic aberrations necessitates large scale detailed analysis of cancer genomes to identify novel potential therapeutic strategies. As part of the International Cancer Genome Consortium (ICGC), the Australian Pancreatic Cancer Genome Initiative (APGI), together with the Baylor College of Medicine and the Ontario Institute of Cancer Research used exomic sequencing and copy number analysis to define genomic aberrations that characterise a large clinically focused prospectively accrued cohort of patients with pancreatic cancer (n = 142). The cohort consists of early (clinical stages I and II) non-pretreated patients with pancreatic ductal adenocarcinoma who underwent operative resection with curative intent. We devise approaches to adjust for low epithelial content in primary tumours and define the genomic landscape of pancreatic cancer to identify novel candidate driver genes and mechanisms. We develop stratified, molecular phenotype guided therapeutic strategies using existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of PC patients. These are then tested in primary patient derived xenografts and cell lines from the above deeply characterised cohort. In addition, we are launching a clinical trial named IMPaCT (Individualised Molecular Pancreatic Cancer Therapy). This trial randomises patients with metastatic disease to either standard first line therapy with gemcitabine, or a molecular phenotype guided approach using next generation sequencing strategies to screen for actionable mutations defined through the ICGC effort.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5071. doi:1538-7445.AM2012-5071
Abstract 5091: Proteomic study using a newly established metastatic lung cancer model
Authors: Wang Dongsheng , Hu Zhongliang , Koenig Lydia , Nannapaneni Sreenivas , Shin Dong M. , Chen Zhuo (Georgia) 
Published: August 2012

Abstract
To understand metastasis of lung cancer, we established a highly metastatic pulmonary large cell carcinoma cell line (801BL) through 2 rounds of in vivo selection using a nude mouse xenograft model. In the first round, low-metastatic human large cell lung cancer cells (801D cell line) were subcutaneously injected into the flank of the mice. Metastatic tumor cells were collected from mouse brain and re-injected into the mice flank in the second round. A highly metastatic cell line 801BL was established from the metastatic cells in the lung. A PCR-based satellite tandem repeat (STR) analysis confirmed the same genomic background of the newly established metastatic cell line 801BL as the non-metastatic counterpart 801C and low-metastatic counterpart 801D cell lines. A xenografted mouse model showed 100% of the mice (8 out of 8 mice) injected subcutaneously with 801BL developed lung metastatic tumors, while none of the mice injected with 801C cells developed lung metastasis (p&lt;0.0001). The metastatic cells present a different cancer stem cell-like morphological feature compared with the 801C and 801D cell lines. Their invasive capability is also increased by 3.47±0.44 fold compared to the non-metastatic counterpart (801C) in a matrigel invasion assay. A stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic study was conducted by comparing the isotopic labeled 801BL cells with non-labeled 801C cells. Bioinformatic analysis using Ingenuity software (http://ingenuity.com) revealed significant alterations in several dominant cell signal networks including cell morphology (p-value:2.80E-09 - 6.83E-03), cellular function and maintenance (p-value:1.08E-08 - 6.83E-03), DNA replication, recombination, and repair (p-value:1.08E-08 - 6.83E-03), and cell death (p-value: 1.88E-08 - 6.83E-03), between the highly metastatic cell line (801BL) and its non-metastatic counterpart (801C). Western blot assay of several proteins from each signaling network confirmed the proteomic findings. Since the highly metastatic cell line and its non-metastatic counterpart share the identical genetic background, the model based on this cell line provides a powerful tool for the study of the mechanisms underlying lung cancer metastasis. (This work is supported by grant from DOD W81XWH-07-1-0306).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5091. doi:1538-7445.AM2012-5091
Abstract 5128: Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data
Authors: Kuijjer Marieke L. , Rydbeck Halfdan , Kresse Stine H. , Buddingh Emilie P. , Roelofs Helene , Bürger Horst , Myklebost Ola , Hogendoorn Pancras CW , Meza-Zepeda Leonardo A. , Cleton-Jansen Anne-Marie 
Published: August 2012

Abstract
High-grade osteosarcoma is a tumor with a complex genomic profile, occurring primarily in adolescents. The extensive genomic alterations obscure the identification of genes driving tumorigenesis in osteosarcoma progenitor cells. In order to identify such driver genes, we integrated DNA copy number profiles (Affymetrix SNP 6.0) of 32 diagnostic biopsies with 84 expression profiles (Illumina Human-6 v2.0) of osteosarcoma as compared with its putative progenitor cells, i.e. mesenchymal stem cells (n=12) or osteoblasts (n=3). In addition, we performed paired analyses between copy number and expression profiles of a subset of 29 patients for which we had both DNA and mRNA profiles. Integrative analyses were performed in Nexus Copy Number Software and statistical language R. Paired analyses were performed on all probes which were significantly differentially expressed in corresponding LIMMA analyses. For both non-paired and paired analyses, copy number aberration frequency was set to &gt;35%. Non-paired integrative analyses resulted in 45 genes that were present in both analyses using different control sets, i.e. MSCs and osteoblasts. 101 genes overlapped between the two paired integrative analyses. Paired analyses detected &gt;90% of all genes found with the corresponding non-paired analyses. Remarkably, approximately twice as many genes as found in the corresponding non-paired analyses were detected. Affected genes were compared with differential expression in osteosarcoma cell lines. An overrepresentation of altered cell division related genes was found, such as MCM4 and LATS2, suggesting that deregulation of the cell cycle is an initial driver of osteosarcomagenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5128. doi:1538-7445.AM2012-5128
Abstract 5151: Transcriptional regulation of the pyruvate dehydrogenase kinase Pdk2 by tumor suppressors
Authors: Contractor Tanupriya , Harris Chris 
Published: August 2012

Abstract
Conversion of pyruvate into lactate despite the presence of oxygen is a hallmark of the Warburg effect, and distinguishes the metabolism of many tumors from the metabolism of many normal cell types. Pdk2, a pyruvate dehydrogenase kinase, facilitates conversion of pyruvate into lactate by inhibiting the pyruvate dehydrogenase complex, which would otherwise convert pyruvate into acetyl-CoA. Previously, Pdk2 activity was thought to be controlled exclusively in a post-translational fashion, through inhibition or activation by metabolites. But in this study we show that two important tumor suppressor pathways, p53 and retinoblastoma, prevent the Warburg effect, and do so through repression of pdk2 transcription. Importantly, a heterologous promoter that drives physiological expression of Pdk2, but disallows repression by p53 or Rb, prevents these tumor suppressors from blocking the Warburg effect. Another consequence of pdk2 repression is increased production of reactive oxygen species, which stimulates p53-dependent apoptosis. We further show that when unable to downregulate Pdk2 expression, p53 can no longer cause apoptosis. Thus two critical features of tumor suppression, apoptosis and pyruvate metabolism, are mediated by repression of pdk2 transcription. This study proves that proper transcriptional regulation of the pdk2 gene is critical for tumor suppression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5151. doi:1538-7445.AM2012-5151
Abstract 5153: Steroid receptor coactivator-2 mediates oncogenic reprogramming of cancer cell metabolism
Authors: Dasgupta Subhamoy , Zhang Bin , Louet Jean-Francois , O'Malley Bert W. 
Published: August 2012

Abstract
Steroid receptor coactivators/p160 (SRC) are frequently amplified and overexpressed in various human cancers which mediate transcriptional functions of nuclear receptors and other transcription factors, providing survival advantage to cancer cells. Recent findings from genomic profiling of human prostate tumors have identified SRC-2 (also known as NCOA2/TIF2), one of the SRC family member as the major oncogene. SRC-2 was found to be significantly enhanced in 8% of primary tumors and 37% of metastatic tumors, and its expression positively correlated with disease recurrence. This suggests SRC-2 oncogene may play crucial role in the development and metastatic progression of prostate cancer. The current study is aimed to understand the molecular function of SRC-2 in the pathogenesis of prostate cancer. RNAi mediated knockdown of SRC-2 in cultured prostate cancer cell lines significantly reduced the cell viability and this phenotype was rescued by ectopic overexpression of SRC-2. Since SRC-2 coactivator is a master regulator of key metabolic pathways in normal cellular physiology, we investigated its role in cancer cell metabolism. Depletion of SRC-2 severely impairs accumulation of lipid droplets, suggesting SRC-2 regulates lipogenesis in cancer cells. Lipid biosynthetic pathways are integral part of cancer cell growth generating fatty acids and cholesterol required for the biogenesis of membrane. Lipids derive majority of carbon chain from glucose flux by diverting pyruvate into acetyl coenzyme A, an important precursor for lipid biosynthesis. Initial screening identified SRC-2 regulates expression of key metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), pyruvate dehydrogenase (PDH), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD1) involved in fatty acid and cholesterol biosynthesis. Interestingly we found expression of HMGCR, FASN and PDH is dramatically increased in metastatic C4-2 cells compared to parental LNCaP cells, and their expression can be reversed by SRC-2 depletion. Ongoing studies will further examine the regulation of glucose and pyruvate metabolism by SRC-2 and its importance in cancer cell metastasis. Although it is well known that many tumours exhibit increased glycolysis, less clear is how associated metabolic pathways are affected and whether they contribute to cancer cell proliferation. These analyses will allow us to identify unpredictable nodes of metabolic regulation by SRC-2 oncogene and may provide rational treatment approaches for targeting tumor metabolism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5153. doi:1538-7445.AM2012-5153
Abstract 53: Tumor-associated macrophage promotes oral cancer progression through activation of Axl signal pathway
Authors: Shieh Yi-Shing , Lee Chien-Hsing , Chen Chi-Kang , Chou Yu-Ting 
Published: August 2012

Abstract
Activation of the receptor tyrosine kinase Axl by its ligand gas6 is implicated in several diseases included inflammation and cancer. Our previous report demonstrated that Axl signal promotes oral squamous cell carcinoma (OSCC) carcinogenesis and progression. Recent studies also suggest that tumor-associated macrophage (TAM) promote tumor growth and metastasis. This study aims to study the potential involvement of Axl signal in the protumoral effect of TAM. We carried out coculture experiment by incubation of oral cancer cells (YD38) and macrophages (THP1). The expression of gas6 and Axl were examined in both cells. Characterized gene expression for M1 and M2 macrophage and EMT gene for cancer were also examined. The effect of Axl signal on cancer cells were further investigated by knockdown Axl expression and neutralized gas6 antibody in coculture system. The association Axl activation (pAxl) and TAM distribution were analyzed by Immunohistochemistry in cancer tissues. Our data indicated that upon coculture with cancer cells, TAM polarized to M2 phenotype with high IL10/low IL12 expression and elevated in gas6 secretion. After coculture with TAM, activation of Axl signal in cancer cells was noted. Furthermore, cancer increased mesenchymal markers expression and invasion/migration ability. While neutralzied gas6 or knockdown Axl, the coculture effects was diminished. In addition our result also demonstrated gas6/Axl signal elevated MMP-2 and -9 through NF-kb pathway to promote tumor invasion/migration, in which coculture of TAM increased NF-kb nuclear translocation and its bonding to MMPs promoter in cancer cells. Finally, in vivo cancer tissues showed significant association between TAM distribution and Axl (phosphorylated) expression. In conclusion, our results showed that TAMs play a protumor role in OSCC. TAM activated Axl signal and promoted tumor progression through NF-kb pathway. Therefore, Gas6/Axl and NF-kb signals in OSCC could be a putative target for therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 53. doi:1538-7445.AM2012-53
Abstract 5306: Overexpression of RAD51 promotes brain metastases from breast cancer
Authors: Woditschka Stephan , Palmieri Diane , Duchnowska Renata , Jassem Jacek , Badve Sunil , Sledge George W. , Steeg Patricia S. 
Published: August 2012

Abstract
Overexpression of the DNA double-strand break (DSB) repair gene RAD51 was identified as part of a 13-gene signature predictive of rapid brain metastasis development (≤3 years vs. &gt;3 years after diagnosis, HR=3.03, p=0.0008) in primary tumors of chemotherapy-naïve HER2+ metastatic breast cancer patients. We also found RAD51 mRNA overexpressed (1.5-fold, p=0.001) in resected brain metastases compared to primary breast tumors from the same patients. In addition, RAD51 expression was significantly higher (1.4-fold, p=0.008,) in brain metastases compared to systemic (bone/lung) metastases. We therefore hypothesize that RAD51 promotes brain metastasis development in breast cancer patients. Given the known role of RAD51 in homologous recombination, important for the repair of DNA DSBs, it was unknown whether RAD51 would promote brain metastasis of breast cancer only in the presence of DNA-damaging chemotherapy or, alternatively, have endogenous biological functions in tumor cells. To functionally evaluate whether RAD51 promotes brain metastases, RAD51 was overexpressed at physiologically relevant levels in a brain-metastatic variants of triple-negative MDA-MB-231 breast carcinoma (231-BR) cells. In vitro, this resulted in a ∼30% increase in clonogenic colony formation (p=0.004), without affecting cell proliferation rates. RAD51 overexpression also conferred chemoresistance to DNA DSB inducing agents such as 25uM carboplatin (p=0.03) and 25nM doxorubicin (p=0.02), but not to agents that do not cause DNA DSBs, such as 2.5nM paclitaxel. In vivo, overexpression of RAD51 in 231-BR cells increased formation of large brain metastases, the equivalent of clinically detectable lesions, (4.0 and 3.3-fold, p=0.01 and p=0.005) and micro-metastases (3.1 and 3.5-fold, p=0.01 and p=0.001) in two independent xenograft experiments. Importantly, this brain-metastasis promoting effect occurred without drugs to induce DSB. This effect was recapitulated in a second animal model based on a brain-metastatic subline of 4T1 murine mammary carcinoma cells (4T1-BR). In this model, RAD51 overexpression increased large brain metastases (3.3-fold, p=0.02) and micro-metastases (2.0-fold, p=0.04) compared to vector control. ShRNA-mediated RAD51 knockdown in 4T1-BR cells resulted in the opposite effect, reducing large brain metastases (1.8-fold, p=0.1) and micro-metastases (2.5-fold, p=0.04). Together these data suggest a driving role for RAD51 in the development of brain metastases from breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5306. doi:1538-7445.AM2012-5306
Abstract 5380: Prophylactic MUC1/Poly-ICLC vaccine in individuals with the history of advanced colorectal adenoma
Authors: Kimura Takashi , McKolanis John R. , Schoen Robert E. , Finn Olivera J. 
Published: August 2012

Abstract
Background MUC1 is aberrantly expressed in a hypoglycosylated form with lack of luminal polarity in variety of human adenocarcinomas including colon cancer. Aberrant MUC1 is also highly expressed in colonic adenomas where it may promote malignant transformation by interacting withβ-catenin known to be an important pathway in colon carcinogenesis. We hypothesized that induction of an immune response against aberrant MUC1 in individuals with a recent history of adenoma may prevent adenoma recurrence and/or their progression to colon cancer. We conducted a clinical study using MUC1 peptide and Poly-ICLC adjuvant vaccine to evaluate the safety and immunogenicity in individuals who are cancer free but at high risk for developing colorectal cancer because of a recent history of advanced adenoma. Method Patients with advanced colorectal adenoma which meets at least one of following criteria: 1) ≥ 1cm in maximal diameter, 2) villous or tubulovillous histology, 3) high-grade dysplasia, were vaccinated with 100μg of 100aa MUC1 peptide (H2N-(GVTSAPDTRPAPGSTAPPAH)5-CONH2) admixed with 500μg of Poly-ICLC (TLR-3 agonist) as adjuvant, on week 0, 2, 10 and one year later. Bloods were collected two weeks after each injection for monitoring of general immunocompetence, development of anti-MUC1 antibody and safety. Results The vaccine was well tolerated without any adverse event grade 2 or higher. Among 36 evaluable patients, anti MUC1 IgG antibody was elicited in 17 patients as measured on week12 (response rate 47.2%). This response rate and the high levels of IgG have never been seen in response to MUC1 vaccines in cancer patients. Antibody titers declined over time but could be boosted to previous or higher levels at 1 year, showing development of immune memory. Vaccine responders were distributed across most HLA-DR and DQ types with similar frequency as in the general population, indicating that the MUC1 peptide could be presented by multiple Class II alleles. Immune competence of colon adenoma patients evaluated by cytokine production of lymphocyte and regulatory T cell frequency was generally equal to healthy individuals, however myeloid derived suppressor cells (MDSCs) were significantly increased in colon adenoma patients. Increase in MDSCs was especially pronounced in non-responders to the vaccine. Conclusion MUC1 poly-ICLC vaccine is highly immunogenic in this prophylactic setting and no significant adverse events have been seen. Vaccine immunogenicity is reduced in individuals with increased numbers of MDSC and this immunosuppressive population might be used as a biomarker to select patients most likely to respond.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5380. doi:1538-7445.AM2012-5380