bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3071: Obesity-associated growth factor signaling upregulates aromatase expression and estrogen receptor activity in breast cancer cells
Authors: Bowers Laura W. , Angel Rebecca De , Tekmal Rajeshwar , Brenner Andrew , Hursting Stephen , deGraffenried Linda 
Published: August 2012

Abstract
Obesity increases the risk of breast cancer by approximately 50% in postmenopausal women and is also associated with a worse prognosis. Elevated estrogen synthesis by the local mammary epithelia and adipose tissue is thought to be the principal mediator of breast tumorigenesis in this population, which primarily develops estrogen receptor alpha (ERα) positive breast cancer. However, the elevated levels of free insulin-like growth factor 1 (IGF-1) that accompany obesity are also thought to play a role. IGF-1 has significant tumorigenic effects in the breast and also regulates aromatase, the key enzyme in the conversion of androgens to estrogen. Consequently, we hypothesized that obesity increases the risk of postmenopausal breast cancer via growth factor-induced aromatase expression and/or activity in the local mammary tissue. We have previously shown that MMTV-Wnt-1 mammary tumors from obese ovariectomized mice express higher levels of aromatase in comparison to tumors from lean ovariectomized mice. To examine the molecular pathways responsible for this effect, we have utilized an in vitro model of obesity in which ERα positive MCF-7 breast cancer cells were exposed to human sera obtained from postmenopausal women and pooled by BMI category. Our data indicates that exposure to obese (BMI ≤ 30 kg/m2) human serum stimulates greater aromatase expression in comparison to control (BMI: 18.5-24.9 kg/m2). This is coupled with enhanced ERα activity when exogenous androgen is present, indicating that the increased aromatase expression results in greater estrogen production. Obese human sera also activates MCF-7 cells’ Akt pathway to a greater degree than control, while MCF-7 cells expressing a constitutively active Akt demonstrate higher levels of aromatase expression in comparison to MCF-7 cells. This suggests that circulating growth factors in the obese sera, like IGF-1, may induce elevated aromatase expression via the downstream PI3K/Akt pathway. To expand on our findings, we plan to assess whether treatment with PI3K/Akt pathway inhibitors eliminates the difference in MCF-7 cells’ aromatase expression following exposure to obese versus control sera. We will also examine how inhibition of the PI3K/Akt pathway affects ERα activity in sera-exposed MCF-7 cells. Through elucidation of the signaling pathways responsible for obesity's upregulation of local aromatase expression, we ultimately hope to develop rational and effective chemopreventive and chemotherapeutic regimens for the high-risk obese postmenopausal population.
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 3071. doi:1538-7445.AM2012-3071
Abstract 3082: TGF-β synergistically stimulates malignant mesothelioma growth with defects in the Hippo pathway by inducing CTGF expression
Authors: Fujii Makiko , Toyoda Takeshi , Nakanishi Hayao , Yatabe Yasushi , Sato Ayuko , Matsudaira Yasue , Ito Hidemi , Murakami Hideki , Kondo Yutaka , Kondo Eisaku , Tsujimura Tohru , Hida Toyoaki , Osada Hirotaka , Sekido Yoshitaka 
Published: August 2012

Abstract
Malignant mesothelioma (MM) arises from the serosal cells of the pleural, peritoneal and pericardial cavities with poor prognosis because of its frequent diagnosis in advanced stages. The primary cause of this disease has often been linked to asbestos exposure, and the number of patients worldwide is expected to peak in the next two decades. There is no known curative therapy for MM and further understanding in molecular mechanism is needed to identify new candidates for targeted treatment. We found that the TGF-β pathway is associated with oncogenic mutations and loss of the tumor suppressor NF2, and induces pro-oncogenic biological activities. Loss of NF2 is one of the genetic lesions which have been related to the growth of human MM. The NF2 gene is responsible for neurofibromatosis type II syndrome and encodes Merlin which negatively regulates YAP function. Nearly 75% MM cases have inactivating mutations in the NF2 gene or in downstream signaling molecules of Hippo signaling cascade. We examined a functional interaction between the Hippo and TGF-β pathways and found that endothelin-1 and connective tissue growth factor (CTGF) are the only proteins affected by these two pathways in MM cells. The CTGF promoter contains both a YAP/TEAD-binding site and a consensus Smad-binding site adjacent to each other. The expression of CTGF induced by TGF-β in MM cell lines was greatly affected by the existence of YAP, by its binding with Smad3, forming a complex on CTGF promoter lesion. Knocking down CTGF expression in MM cells prolonged the survival of mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. This study elucidates a novel molecular mechanism induced by the TGF-β pathway, which may be applicable to malignancies with defective NF2 and of mesenchymal origin.
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 3082. doi:1538-7445.AM2012-3082
Abstract 3088: Essential roles of ATM in GM-CSF-induced bone marrow differentiation to dendritic cells
Authors: So Eui Young , Ouchi Toru 
Published: August 2012

Abstract
The gene mutated in ataxia telangiectasia (ATM) encodes 370-kD protein, belonging to a family of PI-3 protein kinases (PIKKs). ATM has been implicated in cellular responses under conditions of DNA damage that causes DNA lesions, playing crucial roles in activating DNA repair machinery and cell-cycle checkpoints. Recent studies have also illustrated that ATM regulates cellular growth, development, and stem cell renewal. Although mice model has demonstrated that ATM deficiency results in both multiple defects in DNA repair in response to ionizing radiation and severe developmental abnormality in T/B cells development as well as weight-loss, it remains unclear whether ATM is involved in development of other cell lineage. We found that levels of ATM are significantly low in primary bone marrow cells (BMs), and that they are increased when BMs’ are differentiated to dendritic cells (DCs) when stimulated with granulocyte macrophage colony-stimulating factor, GM-CSF. BMs derived from ATM mice (ATM-/- BMs) demonstrate decreased cell proliferation, and their differentiation to DCs is markedly impaired, suggesting that ATM is essential for development of DCs. ATM-deficiency is also associated with a decreased capability of BMs to activate T cells. We also found that an ATM specific inhibitor, KU-55933, abrogated GM-CSF-induced DCs development in BMs cell culture. ATM-deficiency in BMs also resulted in reduced expression of Akt compared with control cells, and inhibited Ser493 phosphorylation of Akt by GM-CSF. Levels of expression and phosphorylation of STAT5 were differentially regulated in ATM-/- BMs, and ectopic expression of STAT5 restored DCs differentiation of ATM-/- BMs. Together, our findings reveal that ATM plays a physiological role in BMs’ differentiation to DCs by regulating Akt/STAT5 pathways.
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 3088. doi:1538-7445.AM2012-3088
Abstract 3092: DSG3 facilitates cancer cell growth and invasion through DSG3-plakoglobin-TCF signaling pathway
Authors: Cheng Ann Joy , Chen Yin Ju 
Published: August 2012

Abstract
DSDSG3 has been reported to act as an oncogene in head and neck cancers (HNCs), but the underlying mechanism of its oncogenic activity is unclear. In this study, we aimed to validate the proposed oncogenic function of DSG3 and investigate its downstream regulatory mechanisms. When we stably transfected HNC cells with a short hairpin DSG3-RNAi (shDSG3) to suppress DSG3 expression, reductions in cell growth and colony formation were observed, in addition to cell cycle arrest at the G0/G1 phase. Both cell migration and invasion abilities were also decreased. BecauseDSG3 is associated with plakoglobin which has been reported as a tumor suppressorin desmosomes, we examined whether or not the phenotypic alterations that occur following DSG3 silencing were mediated through the plakoglobin signaling pathway. Immunoprecipitation and immunofluorescent staining analyses revealed that DSG3 silencing disrupted the interaction of DSG3 with plakoglobin and induced the translocation of plakoglobin from the cytoplasm to the nucleus. Using a luciferase reporter assay and western blot analysis, we found that knockdown plakoglobin increasedTCF transcriptional activity butDSG3 silencing significantly reduced TCF transcriptional activity and subsequently suppressed the expression of the downstream target genes of the TCF transcription factors, including c-myc, cyclin D1, and MMP7, which are involved in the regulation of cell proliferation and invasion. Xenograft mice administered withDSG3 silencing significantly inhibited tumor growth in nude mice and also reduced c-myc, cyclin D1 and MMP7 expression. In conclusion, we found that DSG3 has an oncogenic function in HNC which is through DSG3-plakoglobin-TCF signaling pathway and facilitates cancer growth and invasion. Key words: DSG3, plakoglobin, TCF/LEF promoter, cell growth, cancer invasion
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 3092. doi:1538-7445.AM2012-3092
Abstract 3097: Genomic instability of the breast tumor microenvironment: Stromal alterations or technological artifact
Authors: Rummel Seth K. , Valente Allyson L. , Kane Jennifer L. , Ellsworth Darrell L. , Shriver Craig D. , Ellsworth Rachel E. 
Published: August 2012

Abstract
Introduction: The breast tumor microenvironment plays an active role in tumorigenesis. Molecular alterations, including epigenetic modifications to DNA, and changes in RNA and protein expression have been identified in tumor-associated stroma; however, there is considerable debate as to whether the stroma is characterized by genomic instability or whether detection of chromosomal alterations in the breast stroma is a reflection of technological artifact rather than the true genomic content of the tumor microenvironment. Methods: Surgically-removed breast stroma specimens from 112 women undergoing reductive mammoplasty (n=7), prophylactic mastectomy (N=6) or mastectomy for a diagnosis of breast disease (n=99) were frozen in optimal cutting temperature medium. Allelic imbalance analysis was performed in 484 stromal specimens from 98 women using a panel of 52 microsatellite markers; SNP data was generated from a subset of 86 stromal specimens using 250K SNP arrays (Affymetrix). Copy number alterations were identified using Partek Genomics Suite. Results: AI was not detected in 93% (444/484) of stroma specimens. When compared to AI generated from 77 FFPE stroma specimens, 32 (42%) of which harbored at least one detectable AI event, the frequency of AI in the FFPE specimens (4.62%) was significantly higher (P&lt;0.0001) than that found in frozen specimens (0.45%). Of the stroma specimens assayed using SNP arrays 95% (82/86) had no detectable alterations and the 11 copy number changes were small and not shared between specimens. Conclusions: The data presented here support a model in which the tumor microenvironment is genetically stable. The direct comparison of copy number alterations between FFPE and frozen research-grade specimens using identical methodologies suggests that past reports of significant AI/LOH in breast stroma, both adjacent to and distant from the tumor, reflects artifact in the archival specimens caused by formalin-fixation, paraffin-embedding and tissue storage.
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 3097. doi:1538-7445.AM2012-3097
Abstract 3099: Gastroesophageal junction adenocarcinoma displays abnormalities in homology directed repair
Authors: Dewalt Robin I. , Kesler Kenneth A. , Jalal Shadia I. 
Published: August 2012

Abstract
The incidence of adenocarcinoma of the gastroesophageal (GE) junction has risen dramatically over the last three decades. Outcomes continue to be poor with 5 year survivals estimated at 15%. These poor outcomes are related to the advanced presentation in the majority of patients in addition to the resistance esophageal adenocarcinoma displays to cisplatin based chemotherapy or radiation especially when each is administered alone. Only one-third of patients will have significant benefit and achieve complete responses when treated with the combination of cisplatin-based chemotherapy and radiation followed by surgical resection. Therefore, the need persists for overcoming resistance to cisplatin-based chemotherapy and radiation. Previous studies have highlighted the role of DNA repair pathways in resistance to cisplatin or radiation in a number of solid organ malignancies. The nucleotide repair pathway (NER) repairs the majority of cisplatin-induced DNA lesions while DNA double-strand breaks (DSBs) formed in response to radiation are repaired by homologous recombination (HR) and the non-homologous end-joining (NHEJ) pathways. We hypothesized that cisplatin and radiation resistance in esophageal adenocarcinoma is mediated through abnormalities in these DNA repair pathways. Using paired GE junction adenocarcinoma tumor samples with their matched normal tissue, we analyzed the expression of DNA repair genes in NER, HR and NHEJ pathways using quantitative RT-PCR. We identified overexpression of genes involved in HR in esophageal tumor samples in comparison to their normal counterparts. Eme1, an endonuclease present in complex with Mus81, showed consistent overexpression in GE junction adenocarcinoma samples. Mus81-Eme1 has been shown to play an important role in rescuing stalled replication forks and has been implicated in the repair of interstrand crosslinks, such as those formed in response to cisplatin therapy. Eme1 overexpression in esophageal adenocarcinoma could play a role in resistance to cisplatin through its impact on the repair of cisplatin induced DNA lesions. In addition, Eme1 overexpression could lead to genomic instability contributing to pathogenesis, metastases and therapeutic resistance. Further understanding the implications of Eme1 overexpression in these processes in GE junction adenocarcinoma will be of significant value.
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 3099. doi:1538-7445.AM2012-3099
Abstract 3101: Transition from extrachromosomal to intrachromosomal amplification in glioblastoma cells
Authors: Vogt Nicolas , Gibaud Anne , Debatisse Michelle , Bernard Malfoy 
Published: August 2012

Abstract
Gene amplification is one of the genomic alterations found in cancer cells by which oncogenes may be over-expressed. Amplified sequences may be found within homogeneously staining regions of the chromosomes (hsr) or on autonomously replicating circular and acentric extrachromosomal DNA molecules, named double minutes (dmins). Integration of dmins is a recognized pathway for hsr formation, but the molecular mechanisms involved in this process are still poorly understood. We analyzed three xenografted glioblastomas with dmins at early passages in mice that evolved in hsr at late passages. Using various approaches (FISH, PCR, quantitative-PCR, chromosome walking, DNA sequencing, genome-wide SNP analysis), we characterized the events leading to dmin formation, evolution and reintegration, and determined the structure of the integration sites. In all three glioblastomas, dmins constituted by the fusion of several syntenic or non-syntenic DNA fragments formed upon chromosome fragmentation were present at early passages. The fragments were fused by a non-homologous end-joining (NHEJ) mechanism. Later, a new type of dmin was formed by the fusion of fragments from both the initial dmin and other chromosomes, suggesting a second round of extensive DNA fragmentation. The new type of dmin then gave rise to an hsr. It is not known whether the new dmin was amplified extrachromosomally before reintegration or if one molecule was integrated, then amplified in the chromosome by a mechanism that did not involved breakage-fusion-bridge cycles since the target chromosome was not rearranged outside of the integration site. The integration sites were characterized at the nucleotide level. No preferential integration sequence was found. No significant homologies existed between extrachromosomal and intrachromosomal sequences at the integration sites. The structure of the integration site may be simple, with a single small deletion, or very complex, exhibiting deletions, duplication and insertion of fragments coming from other regions of the genome. Fusions between fragments were mainly driven by NHEJ. Current data allow us to propose a mechanism of hsr formation through integration of extrachromosomal DNA molecules. At the best of our knowledge, it is the first reported molecular characterization of hsr insertion sites.
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 3101. doi:1538-7445.AM2012-3101
Abstract 3179: Targeted re-sequencing of cancer-related genes from matched FFPE and fresh-frozen tumor samples using the Illumina sequencing platform
Authors: Bibikova Marina , Chien Jeremy , Ho Vincent , April Craig , Munchel Sarah , Jaeger Erich , Cooper Samantha , Grocock Russell , Nielsen Fiona , Tarabishy Yaman , Visscher Daniel , Manion Megan , Liu Jonathan , Wieben Eric , Hartmann Lynn , Kalli Kimberly , Shridhar Viji , Fan Jian-Bing 
Published: August 2012

Abstract
High throughput sequencing technologies open up a new dimension in cancer genomics by enabling the characterization of cancer genomes at base-pair resolution. To date, the majority of large-scale genomics projects rely on fresh-frozen biospecimens in their studies, which are difficult to obtain and often lack long-term clinical data. Unlike fresh-frozen samples, archived formalin-fixed paraffin-embedded (FFPE) tissues are more readily accessible, and are often associated with known clinical outcomes and more complete clinical annotations. However, sequencing library preparation methods need to be further optimized with regard to applicability to FFPE samples. To test whether next-generation sequencing technologies could overcome previously reported artifacts associated with formalin fixation and report accurate sequencing results, we compared whole-genome and targeted enrichment DNA sequencing data obtained from five FFPE tumor samples for which matching frozen tissues were available. We successfully generated sequencing libraries using 1 µg of genomic DNA as input material and a modified TruSeq™ sample preparation protocol. We designed a custom enrichment pool targeting exons from 215 cancer-related genes and utilized this pool to pull-down and sequence approximately 1.3 Mb region of the genome with an average 400x coverage depth to test if deep sequencing would improve validation of tumor-specific somatic mutations. We used the Illumina sequence analysis pipeline and the Windows-based second generation DNA sequencing software NextGENe® to analyze the data and identify sequence variations that are different from the human reference genome. CNV detection was overall higher among FFPE samples compared with fresh-frozen samples, demonstrating that tissue processing impacts sequencing data quality. We obtained good concordance in variant calls between matched FFPE and fresh-frozen samples. Discordant variant calls were mainly due to low depth of coverage in the regions where variant calls were made. Improvements to DNA sequencing methods for archived samples will significantly enhance cancer research and will result in more reliable prediction of individual cancer therapies.
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 3179. doi:1538-7445.AM2012-3179