bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3071: Accurate and sensitive detection of KRAS mutations in heterogeneous cancer specimens
Authors: Bao Yun , Merrill David , Corre Delphine Le , Sproul Scott , Ching Bonnie , Casuga Iris , Sapinoso Lorenzo , Desai Sejal , Petraroli Rosella P. , Deng David , Brzoska Pius , Blons Helene , Laurent-Puig Pierre , Chen Caifu 
Published: June 2012

Abstract
The discovery of pivotal genetic alterations and the understanding of their role in cancer is leading to remarkable successes in therapeutics and patient care. Molecular diagnosis methods such as DNA sequencing and conventional genotyping of tumor biopsies have advanced research in this field, but are limited in sensitivity due to stromal contamination and by genetic heterogeneity in cancer. We have recently developed competitive allele specific TaqMan® PCR (castPCR) assays assays for detecting cancer-associated sequence variations. CastPCR not only maintains the wide dynamic range, high sensitivity and reproducibility of TaqMan® assays but also greatly improves the specificity. The technology enables detection, of as little as 1 mutant allele molecule in 10,000,000 wild type molecules. We report here sensitive and accurate detection of cancer-associated KRAS mutations within formalin-fixed paraffin-embedded (FFPE) heterogeneous cancer specimens. Eight FFPE model cell lines were initially used to validate the assays (NCI-H2009:p.G12A; SW1463:p.G12C; PANC-1:p.G12D; PSN-1: p.G12R; A549:p.G12S; SW480:p.G12V; DLD-1:p.G13D; Jurkat:Wild Type). Mutant FFPE cell line DNAs were titrated in the FFPE wild type cell line DNAs from 100% to 0.1%. Mutations were easily identified at the level of 0.1% with high reproducibility. 24 anonymous tumor tissues and 12 non-tumor tissues from FFPE specimens were also examined. No positive samples were found in non-tumor tissues. The results obtained by castPCR for the 24 tumor tissues were concordant to those previously reported by three different methods (Taqman® PCR, Taqman® PCR + PNA and Sequencing). Our results demonstrate that castPCR, as a new rare mutation detection technology, has greater sensitivity, specificity and can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.
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 3071. doi:10.1158/1538-7445.AM2011-3071
Abstract 3082: Exploring LIN28 mRNA targets in breast cancer cells
Authors: Yang Jun , Kinyamu Harriet H. , Archer Trevor K. 
Published: June 2012

Abstract
LIN28 is a RNA binding protein and a pluripotency factor. It represses tumor suppressing microRNA let-7 and thus derepresses let-7 oncogene targets such as HMGA2, K-Ras and c-Myc. In addition, LIN28 binds and enhances translation of IGF-2 mRNA a known mitogen. Recent reports show that LIN28 overexpression promotes tumor cell migration and cellular transformation through repression of let-7, and that overexpression is associated with advanced stages of disease, including breast cancer. Despite the apparent critical role in cancer, the molecular function and mode of action of LIN28 is not yet elucidated. To further understand the function of LIN28, we explored LIN28 mRNA targets in breast cancer cells using RNA-protein immunoprecipitation (RIP-Chip) followed by RNA sequencing. Using RIP-Chip and RNA sequencing we have identified a number of novel LIN28 targets in MCF-7 breast cancer cells. Therapeutic drugs inhibiting LIN28 could be promising in treatment of cancer. Our experiments also demonstrate that MG132, a proteasome inhibitor, inhibits LIN28 expression and modulates expression of LIN28 mRNA targets in breast cancer cells. The mechanism by which LIN28 regulates its targets is unknown; however, a number of the new targets are important in cancer. Previous studies suggest that LIN28 acts through translational mechanisms. Studies are ongoing to reveal the mechanisms by which LIN28 regulates bound targets and how proteasome inhibitors impact this regulation.
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 3082. doi:10.1158/1538-7445.AM2011-3082
Abstract 3083: The RNA stability factor HuR promotes an angiogenic switch in colon cancer
Authors: Young Lisa E. , Dixon Dan A. 
Published: June 2012

Abstract
The initiation and progression of colorectal tumorigenesis is characterized by alterations in gene expression that allow for the overexpression of oncogenic and tumor-promoting factors. In normal cells, the mRNA transcripts of these cancer-associated genes are targeted for rapid decay through AU-rich elements (ARE) present in the mRNA 3’ untranslated region (3′UTR). However, growing evidence reveals that the loss of ARE-mediated mRNA decay is a characteristic feature contributing to pathogenic gene expression in colorectal cancer. Our prior work identified enhanced expression of the RNA-binding protein HuR to occur during colon tumorigenesis and HuR overexpression is correlated with poor clinical prognosis. In this capacity, HuR promotes overexpression of many cancer-associated factors by binding to their ARE and interfering with subsequent rapid mRNA decay. To determine the functional significance of HuR overexpression in vivo, a tissue-specific HuR-transgenic mouse (HuR-Tg) was created that overexpresses HuR in the epithelium of the small intestine and colon. HuR-Tg mice displayed normal growth and did not reveal any morphological changes in the gastrointestinal tract. To test if HuR overexpression can impact tumorigenesis downstream a tumor initiating event, crosses between HuR-Tg mice and the APCMin/+ mouse, a genetic model of gastrointestinal tumorigenesis, were performed. As early as 12 weeks of age, HuR-Tg/APCMin/+ lines display a 2- to 4-fold increase in tumor burden and size in both the colon and small intestine compared to APCMin/+control mice. Based on HuR's ability to bind various ARE-containing mRNAs associated with angiogenesis, vascular density was assayed in tissue derived from HuR-Tg/APCMin/+ mice. Micro-vessel density was 2-fold greater in the tumors and surrounding tissue in APCMin/+ mice overexpressing HuR. Angiogenic mRNA array analysis of tumors derived from HuR-Tg/APCMin/+ mice showed enhanced expression of multiple ARE-containing angiogenic genes including the HuR target genes vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Furthermore, dietary treatment of HuR-Tg/APCMin/+ mice with celecoxib attenuated HuR-dependent tumor formation and suppressed micro-vessel density and VEGF expression. These findings indicate that HuR functions during colon tumorigenesis downstream of a tumor-initiating event to stabilize ARE-containing mRNAs associated with tumor vascularization and identify this mRNA stability factor as a new molecular target for therapeutic intervention in controlling angiogenic gene expression.
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 3083. doi:10.1158/1538-7445.AM2011-3083
Abstract 3089: The role of p63 regulation during epithelial to mesenchymal transition (EMT) and subsequent accumulation of malignant features of primary immortalized prostate cells
Authors: Olsen Jan Roger , Ke Xi-Song , Qu Yi , Rostad Kari , Hellem Margrete R. , Lorens James B. , Micklem David R. , Haugen Hallvard , Gravdal Karsten , Halvorsen Ole Johan , Rotter Varda , Akslen Lars A. , Oyan Anne Margrete , Kalland Karl H. 
Published: June 2012

Abstract
A family of transcription factors is constituted by p53, p63 and p73. Unlike p53, which is expressed in response to environmental stress, p63 (TP73L) is constitutively expressed at high levels in a variety of epithelial tissues including prostate. Our genome-wide gene expression analysis identified p63 as one of the most consistently under-expressed genes in prostate cancer samples compared to matched benign prostate tissue. All benign prostate samples including benign prostate hyperplasias (BPH) exhibited high p63 expression.
Two alternative p63 promoters generate two different N-terminal variants, TA or ΔN which contains and lacks the transactivating domain, respectively. Differential splicing generates multiple additional isoforms. The activity and interactions of the different isoforms remain unresolved.
Using isoform-specific TaqMan real-time quantitative PCR assays, we have found that ΔNp63α is the predominant isoform in prostate tissues, but the other isoforms are detectable.
Our group has established a new experimental cell culture model based upon primary, immortalized prostate epithelial cells (EP156T cells), where p63 was found to be shut-down as EP156T cells underwent epithelial-to-mesenchymal transition (EMT) to become EPT1 cells. Subsequently, EPT2 cells were derived from EPT1 cells and p63 stayed shut-down. EPT2 cells had acquired several malignant features in contrast to the progenitors, including anchorage independent growth in soft agar and ability to grow at much higher density in monolayers.
To dissect the role of p63 in EMT and in gene expression modules associated with carcinogenesis, we have stably re-expressed the predominant isoform ΔNp63α in both EPT1 and EPT2 cells using retroviral vector transductions.
Microarray analysis shows that p63 re-expression leads to re-expression of genes participating in several cell-junction components, such as hemidesmosomes, focal adhesions and gap junctions. These genes were down-regulated during EMT. There were also morphological changes and a decreased ability to migrate following p63 re-expression. This indicates that ΔNp63α re-expression might result in a partial mesenchymal-to-epithelial transition (MET).
The present focus is to identify co-factors that may act complementary or synergetically with p63 to induce a complete MET in EPT1 cells and to identify p63 target genes and regulatory cross-talk with relevance for anti-cancer strategies.
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 3089. doi:10.1158/1538-7445.AM2011-3089
Abstract 3100: HOX transcription factors promote cell survival in breast cancer
Authors: Morgan Richard , Michael Agnieszka , Bhatt Aagna , Harrington Kevin , Boxall Angela , Annels Nicola , Pandha Hardev 
Published: June 2012

Abstract
The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. Whilst relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumour suppressors, and also redundant, with several genes essentially having the same function. Here we have attempted to address this complexity by using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumours to HXR9 or its derivatives. Furthermore, we show that whilst HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumour-suppressor properties of a subset of HOX genes in breast cancer.
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 3100. doi:10.1158/1538-7445.AM2011-3100
Abstract 3103: Transducin β-like protein 1 promotes cancer cell invasion by recruiting nuclear factor-κB to target gene promoter for transcriptional activation
Authors: Ramadoss Sivakumar , Li Jiong , Ding Xiangming , Wang Cun-Yu 
Published: June 2012

Abstract
Background and Purpose: Nuclear factor-kappaB (NF-κB) signaling controls a wide range of cellular functions such as tumor progression and invasion by inducing gene expression. Although significant progress has been made in understanding NF-κB-mediated gene transactivation, little is known about how NF-κB is recruited to its target gene promoters. Therefore the purpose of the study is to determine the role of transducin β-like protein 1 (TBL1) in the recruitment of NF-κB to target gene promoter. Methods:TBL1 knock down breast and squamous cell carcinoma cells were used to asses the significance of TBL1 depletion on NF-κB recruitment to target gene promoter and its consequence on the invasion of cancer cells. Results: Our results revealed that transducin β-like protein 1 (TBL1) controlled the expression of NF-κB target genes by directly binding with NF-κB and facilitating its recruitment to target gene promoters. TNF-α stimulation triggered the formation of NF-κB and TBL1 complex and subsequent target gene promoter binding. Knock-down of TBL1 impaired the recruitments of NF-κB to its target gene promotes. Interestingly, the mRNA microarray studies available from Oncomine revealed that TBL1 expression levels were higher in invasive breast cancer tissues than in breast adenocarcinoma. Consistently, TBL1 knockdown significantly reduced the invasive potential of breast cancer cells by inhibiting NF-κB. Conclusions: Our results unravel a new mechanism for the regulation of NF-κB activation, with important implications in the development of novel strategies for cancer therapy by targeting NF-κB.
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 3103. doi:10.1158/1538-7445.AM2011-3103
Abstract 3106: Intestinal mesenchymal fibroblasts promote early epithelial tumorigenesis through activation of integrin beta4 and receptor tyrosine kinases, bypassing common mutational mechanisms
Authors: Woo Janghee , Morikawa Teppei , Ogino Shuji , Gilliland D. Gary , Shivdasani Ramesh A. 
Published: June 2012

Abstract
Cancer cells communicate extensively with their stroma, exchanging signals that influence growth and metastasis. Intestinal sub-epithelial myofibroblasts (ISEMFs) direct organogenesis and constitute the colorectal cancer (CRC) microenvironment. ISEMFs from the mouse small intestine and colon express regional characteristics and different cytokines. In line with these regional patterns, ApcMin mice develop adenomas principally in the small intestine but not in the colon; conversely, humans develop tumors mainly in the colon and rarely in the small bowel. We hypothesize that intestinal ISEMFs influence tumor regionality through cell-cell communication. Murine ileal ISEMFs supported growth of human CRC cells markedly better than those originating in the colon in NOD/SCID xenografts and in vitro. We traced this effect to a single secreted factor, matrix metalloproteinase 9 (MMP9), which is exclusively mesenchymal in expression and substantially enriched in native ileal over colonic ISEMFs. Actively cycling intestinal epithelial progenitors and Lgr5+ stem cells showed selectively reduced bromodeoxyuridine uptake in Mmp9-/- mouse ileum, revealing that Mmp9 deficiency impairs epithelial self-renewal. Moreover, ApcMin mice developed fewer ileal adenomas upon treatment with an Mmp9 inhibitor or on the Mmp9-/- genetic background. MMP9 immunohistochemistry revealed expression in 106 of 642 (16.5%) human CRC samples; expression was confined to stromal fibroblasts and considerably enriched among CRCs that lack characteristic KRAS mutations and harbor the CpG island methylator phenotype. Gene expression in epithelial cells interacting with ileal fibroblasts pointed to activation of cytoskeletal remodeling and integrin ß4 signaling pathways, signatures absent in cells cultured with colonic ISEMFs. Biochemical assays verified that stromal MMP9 activates epithelial integrin ß4 and, in turn, ErbB and c-Met receptor tyrosine kinases (RTKs) in adjoining epithelial, including human CRC, cells. This activation is mediated by MMP9 cleavage of the integrin ligand laminin alpha4. Activation of epithelial integrin ß4 and RTKs and the paucity of KRAS mutations in CRCs with stromal MMP9 expression together suggest that potent MMP9-mediated microenvironment signals can help bypass common mutational mechanisms of constitutive growth factor pathway activation in CRC. These results define a novel and therapeutically tractable pathway of tumor-stromal interaction in early CRC pathogenesis.
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 3106. doi:10.1158/1538-7445.AM2011-3106
Abstract 3111: Normal breast epithelial architecture and breast-cancer cell metabolism are altered by adipocytes and inflammatory fatty acids: Implications for postmenopausal breast cancer
Authors: Siriwardhana Nalin , Layman Rhett , Patel Shiwani , Karwandyar Ayub , Clark Matthew Mitchell , Tatge Blair Blair , Lampley Jessica , Zou Ming-Hui Ming-Hui , Wang Qilong , Moustaid-Moussa Qilong Moustaid-Moussa Naima , Wimalasena Jay 
Published: June 2012

Abstract
Alteration of organized breast epithelial ductal architecture accompanies neoplastic transformation. Obesity and chronic inflammation are associated with increased risk of postmenopausal breast cancer (BC). Further, omega 6 arachodonic acid (AA) significantly increases the secretion of pro-inflammatory cytokines by adipocytes compared to omega 3 eicosapentaenoic acid (EPA), therefore, we compared the effect of adipocytes and these two fatty acids on primary breast epithelial cell growth and formation of acini-like spheroid architecture. We used three dimensional (3D) MatrigelTM cultures of both basal and luminal primary breast cells and a novel 3D co-culture system with primary breast epithelial cells (basal/luminal) and adipocytes from lean or obese women. Effects of adipocytes as well as fatty acids on cellular architecture were assessed. Culture of basal or luminal epithelial cells with obese adipocytes/AA showed a significant increase in the irregularity of acini-like spheroid formation compared to normal spheroid formation in the absence of adipocytes or AA. Conditioned media transfer from lean/obese adipocytes into growing breast cell cultures showed remarkably different effects on LKB1/AMPK/mTOR metabolic signaling systems specifically in invasive MDA MB 321 cells. Obese adipocyte media decreased the activation of LKB1, AMPK, Acetyl-CoA carboxylase (ACC) and mTOR levels compared to lean adipocyte media. Further the expression of LKB1, pLKB1, pACC and mTOR were significantly higher in MDA MB 231 cells compared to less invasive MCF7 or epithelial MCF10A cells. Our data highlights the regulatory influence of adipocytes and inflammatory fatty acids on breast cellular architecture as well as metabolism and such alterations may underlie the effects of obesity on transformation of normal breast cells to BC cells.
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 3111. doi:10.1158/1538-7445.AM2011-3111
Abstract 3119: SIDT1 is a mediator of pro-desmoplastic pancreatic stellate-adenocarcinoma intercellular communication
Authors: Duxbury Mark S. , Christie Jennifer 
Published: June 2012

Abstract
Introduction: Pancreatic adenocarcinoma is characterized by extensive collagen-rich but hypovascular desmoplasia that impairs drug delivery. Desmoplasia is driven by complex tumor-stromal interactions. Anti-desmoplastic strategies may improve therapeutic responses to existing agents. We examined the role of the membrane protein SIDT1 in mediating pro-desmoplastic signaling between tumor and stromal cells.
Methods: Pancreatic stellate cells (PSC) and adenocarcinoma cells were isolated from surgical patients, characterised and maintained in culture. SIDT1 and collagen I expression was quantified by realtime PCR and Western blotting. SIDT1 fluorescence immunocytochemistry and immunohistochemistry was performed. Collagen I production was quantified in direct and indirect adenocarcinoma/PSC coculture. The effects of SIDT1 gene silencing on collagen I expression were examined using doxycycline-inducible shRNA generating vectors and compared to non-silencing control transfectants
Results: SIDT1 is expressed at relatively high levels in PSC. Adenocarcinoma cells and patient specimens show heterogeneity in SIDT1 expression. Adenocarcinoma/PSC coculture enhances collagen I expression. SIDT1 gene silencing, but not control shRNA, attenuates collagen I production in direct but not indirect coculture.
Conclusions: SIDT1 is abundant in PSC and variably expressed in patient samples. SIDT1 gene silencing limits collagen I production driven by contact dependent tumour-stromal intercellular communication. Disruption of SIDT1-dependent adenocarcinoma/PSC communication may represent a means of limiting desmoplasia.
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 3119. doi:10.1158/1538-7445.AM2011-3119