bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1082: Stochastic control of abnormal morphogenesis induced by the ErbB2 oncoprotein
Authors: Wang Lixin , Janes Kevin 
Published: August 2012

Abstract
Activation of the receptor tyrosine kinase ErbB2 causes multiacinar structures in 3D culture that are reminiscent of early-stage breast tumors. The penetrance of the multiacinar phenotype is incomplete and random, and dimerization with other ErbB family members gives rise to quantitative differences in penetrance. Our goal is to understand the mechanism by which a multiacinus initiates and why only a random fraction of the cultured acini exhibit the morphogenetic defect when ErbB2 is activated. Our working hypothesis is that acute differences (dichotomies) in gene expression develop among acini and give rise to the distinct 3D phenotypes induced by ErbB2. The transcriptional dichotomies that exist before the appearance of the multiacinar phenoptype will be the ones most likely to control it. We are using a new technique, called “stochastic profiling,” that our lab developed for discovering transcriptional dichotomies in a seemingly uniform cell population. We have established single ErbB2 dimer clones with similar expression levels of ErbB2 and its dimerization partner. Expression of the ErbB2 constructs was also validated at the single-cell level in frozen acinar sections by RNA FISH. Laser capture microdissection was used to select a small number of cells (10-100 cells) from the fresh frozen 3D sections followed by RNA extraction and small-sample cDNA amplification. The amplification parameters were optimized for the ErbB2 clones in different culture formats. We observed good quantitative linearity and amplification efficiencies for a wide range of high- and low-abundance targets in a 2D-culture format. We are working to improve the amplification efficiency of samples microdissected in the 3D-culture format. The long-term goal is to link upstream acinus-specific expression programs to downstream morphogenetic heterogeneities. The results from this project could explain mechanistically why only a fraction of ErbB2-overexpression breast cancers respond positively to ErbB2-targeted therapeutics.
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 1082. doi:1538-7445.AM2012-1082
Abstract 1086: Discoidin domain receptor 1 contributes to tumorigenesis through modulation of TGFBI expression
Authors: Rudra-Ganguly Nandini , Satpayev Daulet , Lowe Christine , Hu Liping , Randhawa Bally , Chang Mi Sook , Verlinsky Alla , Coleman Jeffrey , Challita-Eid Pia , Yang Peng , An Zili , Morrison Karen , Raitano Art , Pereira Daniel S. , Stover David 
Published: August 2012

Abstract
Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family. It is activated by binding to its ligand, collagen and plays a key role in cell survival, adhesion, migration and invasion. Although DDR1 is present in several normal tissues, it is overexpressed in various cancer types, including lung, colon, ovary and breast tumors as well as in gliomas, where it is known to be associated with poor prognosis. The significance of DDR1 in cancer was illustrated using shRNA silencing, which impaired tumor cell growth, both in vitro and in vivo. Using microarray analysis of tumor cells with DDR1 knockdown, we identified an upregulation of TGFBI expression, which was subsequently confirmed at the protein level. TGFBI is a TGFβ induced extracellular matrix protein secreted by tumor cells and has been reported to act as either a tumor promoter or suppressor, depending upon tumor type. Exogenous addition of recombinant TGFBI to tumor cells inhibited clonogenic growth, recapitulating shRNA data. When grown in vivo as xenografts, the DDR1 knockdown cell lines demonstrated a similar phenotype of reduced growth and tumors exhibited an increase in TGFBI protein levels. In summary, our data suggests that DDR1 expression levels influences tumor growth in part through modulation of TGFBI expression. Ongoing studies will help to understand how DDR1 and TGFBI are linked and contribute to tumorigenesis.
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 1086. doi:1538-7445.AM2012-1086
Abstract 1087: TGF-β activated EGFr as a bypass mechanism for the acquired resistance of MET inhibitors in hepatocellular carcinoma
Authors: Rountree Carl B. , Ding Wei , Dang Hien , Steinway Steve 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) patients with an active HGF/c-Met signaling pathway have a significantly worse prognosis. Although targeting strategies using MET tyrosine kinase inhibitors (TKI) are in Phase I/II testing for HCC, monotherapy using TKIs in other cancers has not demonstrated durable responses. In non-small cell lung cancer, bypass mechanisms for resistance to EGFr TKIs include MET amplification and activation. We utilized human HCC MET+ cell lines to explore a mechanism of EGFr activation during MET inhibition, and we examined the effect of combination MET and EGFr TKI therapy on suppressing this bypass mechanism in HCC in vivo. Analysis of 149 HCC specimens using transcriptome profiling and immuno-histochemical staining demonstrates a strong negative correlation between EGFr and MET expression. HCC is predominantly either MET positive [44%] or EGFr positive [45%], and co-expression of MET and EGFr is extremely rare in the same tumor. We have previously demonstrated that treatment of xenograft tumors of human HCC MET+ MHCC97-H cells with a MET TKI resulted in stasis of tumor growth in vivo (You … Rountree. Hepatology. 2011). To understand the mechanism of survival in the MHCC97-H cells after inhibition of MET, we developed an MHCC97-H cell line with stable expression of MET shRNA. This MHCC97-H METneg line demonstrated the slower growth kinetics and the inhibition of both PI3K and MAPK signaling comparable to MET TKI treated xenografts. Screening against 850 kinases and phosphatases identified EGFr activation as a mechanism of survival in this MHCC97-H METneg line. Gene expression analysis of this MHCC97-H METneg cell line demonstrated a 6 fold increase in TGF-β, a ligand of EGFr. MHCC97-H xenograft tumor analysis demonstrates a 20 fold increase in TGF-β expression after MET TKI therapy. In vivo treatment of MHCC97-H tumors with combination MET and EGFr TKI therapy resulted in complete regression of all small tumors (15 mm3 at start of TKI) compared to partial regression when MET TKI was used as monotherapy. Treatment of large tumors (200-300 mm3 at start of TKI) with combination TKI therapy resulted in a significant reduction in tumor volume compared to MET TKI monotherapy. EGFr TKI monotherapy had no effect on tumor growth kinetics. Within MET positive HCC models, MET TKI therapy results in a bypass mechanism through up-regulation of TGF-β and activation of EGFr. This bypass mechanism can be partially overcome with combination EGFr and MET TKI therapy.
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 1087. doi:1538-7445.AM2012-1087
Abstract 1092: Targeting multiple receptor tyrosine kinases in ovarian cancers
Authors: Ou Wenbin , Jiao Yisheng , Meng Fanguo , Zhou Haimeng , Wang Aiyuan 
Published: August 2012

Abstract
Ovarian cancer is a leading cause of cancer death among women in Western Europe and the United States, which has the highest mortality rate of all gynecologic malignancy. Although more than 70% patients have increased 5-year survival rates after surgery followed by chemotherapy and second-line therapies, the low overall cure rates and the intolerable side effects of systemic chemotherapy asks for the development of novel and more effective pharmacological interventions. The increasing evidences suggest that receptor tyrosine kinase (RTK) activation participates in the oncogenic progression from nonneoplastic mesothelial lining of the ovaries or the fallopian tube epithelium to epithelial ovarian cancer. The RTKs, including EGFR, ERBB2, PDGFR, VEGFR and MET, are activated in subsets of ovarian cancer, suggesting that these kinases might represent novel therapeutic targets. However, clinical trials have not or just partially shown benefit to ovarian cancers treated with EGFR, ERBB2, or PDGFR inhibitors. Despite multiple RTK activation in ovarian cancer pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. We hypothesized that a coordinated network of multi-RTK activation is important for the tumorigenesis of ovarian cancers. Herein, we demonstrate co-activation of multiple RTKs (EGFR, ERBB2, ERBB4, MET and/or AXL) in individual ovarian cancer cell lines and primary tumors. We also show that coordinate inhibition of this multi-kinase signaling has substantially greater effect on ovarian cancer proliferation and survival, compared to inhibition of individual activated kinases. The inhibition of this multi-RTK signaling by HSP90 suppression results in profound pro-apoptotic and anti-proliferative effects, and is associated with the inactivation of RTK downstream PI3-K/AKT/mTOR and RAF/MAPK signaling. These studies suggest that anti-multiple RTK strategy could be useful in the treatment of ovarian 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 1092. doi:1538-7445.AM2012-1092
Abstract 1097: MicroRNA expression in white blood cells of CML patients: Differential expression in responders and non-responders to imatinib
Authors: Bruhn Oliver , Diewock Tobias , Pott Christiane , Kneba Michael , Cascorbi Ingolf , Haenisch Sierk 
Published: August 2012

Abstract
Introduction: Treatment of chronic myeloid leukemia (CML) with the BCR/ABL-inhibitor imatinib led to a tremendous progress of over-all survival. However therapy resistance in a significant proportion of patients remains a severe clinical problem. Aside mutations of the BCR/ABL gene, regulation of cellular transporters or downstream factors may contribute to non-response. We aimed to investigate micro-RNA expression profiles in peripheral leukocytes of 21 newly diagnosed CML patients without BCR/ABL-mutations in order to identify biomarkers to treatment-response of imatinib. Methods: Ten responders (molecular remission) and 11 non-responders were included. Expression of 667 microRNAs was analyzed using a TaqMan Low-Density Array system. Relative fold change of microRNAs between groups was calculated according to the 2^-ΔΔCt method. MicroRNAs with a fold change&gt;2 and a P-value&lt;0.01 were considered significant. MicroRNAs with minor expression (Ct-value&gt;20) were not included. Putative targets of dysregulated microRNAs were considered, if predicted by at least three databases, and further analyzed using the DAVID-bioinformatic database. Results: Four microRNAs were significantly deregulated (miR-7, miR-744*, miR-616, miR-212) between responders and non-responders, when being treatment-naïve, predicted to have 97 potential targets. In depth target analysis showed that transcription regulators (21% of the predicted targets) are highly enriched compared to normal gene expression background of humans. Pathway analysis revealed six genes involved in cancer pathways, whereas four of them are directly involved in the chronic myeloid leukemia pathway (SMAD4, NRAS, RB1, RAF1). In responders seven microRNAs were deregulated before and after therapy, whereas five other microRNAs were deregulated within the group of non-responders. Three deregulated microRNAs were identified in both groups. Most predicted target genes are involved in MAPK signaling and exocytosis, 13% of the targets were predicted to be transcription regulators, and 18% cellular (especially uptake) transporters. Conclusion: We identified distinct microRNA pattern comparing blood samples of responders and non-responders prior to imatinib therapy. Predicted target genes were primarily transcription factors and oncogenes. In contrast, transporters and exocytotic pathways are in addition frequent targets of microRNAs deregulated after imatinib therapy. The suitability as biomarkers for prediction of imatinib-response requires further confirmation.
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 1097. doi:1538-7445.AM2012-1097
Abstract 1104: Nuclear translocalization of DICER correlates with high-risk clinical/histologic features in melanoma
Authors: Chakravarti Nitin , Prieto Victor , Bassett Roland 
Published: August 2012

Abstract
Melanoma is an aggressive malignancy with a relatively high metastatic rate, responsible for almost 60% of lethal skin tumors. Despite numerous efforts, there is still a need to better understand the molecular pathways involved in malignant melanoma metastasis. In recent years, there have been several studies highlighting the role of deregulated microRNAs (miRNAs) expression in tumor progression and metastasis. DICER is a central regulator of miRNA maturation and recently, has been shown to be upregulated in cutaneous melanoma at both protein and mRNA level. Arur et al. [1], reported DICER to be one of the ERK substrate, and this activation results in its nuclear translocalization (personal communication). However, it is unknown whether differential cellular expression of DICER contributes to the pathogenesis of melanoma. In order to test the hypothesis that aberrant nucleo-cytoplasmic expression of DICER plays a significant role in melanoma progression, we have performed semiquantitative immunohistochemical analysis of DICER in benign nevi (n=17), primary melanomas without metastasis (n=38) and with metastasis (n=27), and melanoma metastases (n=34 cases). A significant positive correlation was observed between the percentage of positive cells (p=0.003) and staining intensity (p=0.01) for nuclear DICER with progression from benign nevi to primary melanoma. Interestingly, primaries without metastasis had significantly higher levels of DICER immunopositivity in tumor cells than primaries with metastasis (p=0.02). Furthermore, metastatic melanomas showed significantly larger number of cells having intense immunoreactivity for DICER protein in nucleus than the primary melanomas (p=0.02). Significantly larger percentage of tumor cells showing DICER expression in the nucleus were observed in those lesions having ulceration (p=0.007) and vertical growth phase, which are well-established markers of poor clinical outcomes in patients with cutaneous melanoma. On the other hand, lesions showing no vascular invasion expressed higher levels of DICER in the cytoplasm (p&lt;0.0001). Disease-specific survival was significantly shorter in patients with increased nuclear expression of DICER (p=0.04). Thus, differential cellular localization of miRNA-regulating DICER protein correlates with disease progression and high-risk clinical and histologic features in melanoma. Therefore, it will be interesting to further delineate the role of nuclear DICER in melanoma. References 1. Arur S, Ohmachi M, Nayak S, et al. Proc Natl Acad Sci U S A. 2009 Mar4;106(12):4776-81.
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 1104. doi:1538-7445.AM2012-1104
Abstract 1105: MicroRNAs and their targets genes promote cisplatin resistance in epithelial ovarian cancer cells
Authors: Vargas Ileabett M. Echevarria , Valiyeva Fatma , Vivas-Mejía Pablo 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are 21-25 nucleotides regulatory involved in silencing mRNAs in a sequence specific manner. Accumulated data has established the central role of various microRNAs in tumor initiation and progression. Furthermore, recent studies revealed that microRNAs participate in the resistance of cancer cells to different chemotherapeutic agents. In ovarian carcinoma, the fifth cause of cancer deaths in US, it has been shown that several miRNAs contribute to drug resistance. However, the role of these miRNAs in the cisplatin resistance of ovarian cancer cells is unclear. In a microarray study, we found that miR-21, miR27b and miR-622 were upregulated in the A2780CP20 cisplatin resistant ovarian cancer cells compared with the A2780PAR cells, which are sensitive to cisplatin treatment. Real-time PCR studies confirmed these findings. Opposite, the c-Jun transcription factor was upregulated in this microarray analysis. Then, we used TargetScan and miRBase tools to identify miR-21, miR-27b and miR-622- target genes. Interestingly, several of these miRNA-target genes were identified as downregulated in our microarray study. These results were corroborated by Western blot analysis. Moreover, cell survival experiments in the presence of a miR-21 mimic, made A2780PAR cells more resistant to cisplatin treatment. These results indicate that dysregulation of various miRNAs and their target genes contribute to the cisplatin resistance of ovarian cancer cells.
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 1105. doi:1538-7445.AM2012-1105
Abstract 1106: Targeting both non-coding and coding sequences with small RNA efficiently knocks down DNA repair genes and radiosensitizes human tumor cells
Authors: Zheng Zhiming , Wang Ya , Zhang Xiangming 
Published: August 2012

Abstract
During radiotherapy, human tumor cell death is mainly caused by ionizing radiation (IR)-induced DNA double strand breaks (DSBs). In general, human cells use two pathways: homologous recombination repair (HRR) and non-homologous end-joining (NHEJ), to repair DNA DSBs. However, in many cases, human tumors are resistant to IR due to the abnormal up-regulation of DNA DSB repair genes. Previously it was reported that using a siRNA approach could knock down the DNA DSB repair genes and sensitized the tumor cells to IR, however, the levels of knock down using a siRNA approach alone is limited. Here, we developed a novel combined approach using an artificial microRNA (amiR) to target the 3′-untranlated region (UTR) of the DNA DSB repair gene, XRCC2 (a HRR factor) or XRCC4 (a NHEJ factor), and the siRNA to target the coding region of the gene in different human tumor cell lines. Our results indicate that the combined approach is much more efficient than the amiR or siRNA approach alone in knocking down the targeted gene and sensitizing human tumor cells to IR-induced killing. The amiR decreased the targeted gene through reducing the mRNA stability and blocking the translation. These results demonstrate that the combined approach could be used for many different purposes to knock down genes in different cell lines, especially genes that are difficult to knock down using amiR or siRNA alone.
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 1106. doi:1538-7445.AM2012-1106
Abstract 1108: Subtype specific expression of immnune-modulating miR-155 and miR-146a in anaplastic large cell lymphoma
Authors: Merkel Olaf , Griessl Robert , Hamacher Frank , Grabner Lisa M. , Greil Richard , Kenner Lukas 
Published: August 2012

Abstract
Anaplastic large-cell lymphoma (ALCL) is a mature T-cell malignancy that is subdivided further into two distinct disease entities based on the presence or absence of the anaplastic lymphoma kinase (ALK) fusion protein. ALK+ ALCL bears the t(2;5) (p23;q35) translocation in greater than 80% of cases, which results in the expression of the chimeric nucleophosmin (NPM)-ALK. This leads to the activation of many different growth-promoting and anti-apoptotic pathways, including PI3K/Akt1/mTOR, Jak/Stat and AP-1. Recently, micro-RNAs (miRNAs) have emerged as tiny but potent molecules to regulate cell differentiation and proliferation. In a recent publication we have reported that miR-155 is up-regulated in ALK+ and down-regulated in ALK- ALCL. We have now identified an additional miRNA, miR-146a, that is significantly higher expressed in ALK- ALCL. Both miRNAs are strongly induced by T-cell activation. We report here that in ALCL cell lines that highly express miR-155 (like ALK- Mac1 and Mac2a) its target protein CCAAT-enhancer-binding protein ≤ (C/EBPβ) is suppressed and moreover reintroduction of miR-155 in cell lines that have low miR-155 levels (Karpas-299, SR786, SU-DHL-1, SUP-M2) can actively down-regulate C/EBPβ. Conversely, high expression of miR-146a in primary ALK- ALCL FFPE specimens corresponds to low expression of its target protein IL1 receptor-associated kinase 1 in ALK - cell lines. Due to the known roles of miR-155 and miR-146a we assessed cytokine release in a set of ALCL cell lines with and without the ALK translocation. Interestingly, we found expression of cytokines including IL-6, IL-10, IL-21 and IL-22 in ALCL cell lines. Inflammatory cytokines IL-6, IL-21 and IL-22 were 4 to 10-fold higher in ALK- cell lines, whereas anti-inflammatory IL-10 levels were not related to ALK status. Reintroduction of miR-155 into the ALK+ cell lines Karpas-299 and SR786 was able to enhance expression of IL-22. To test the influence of miR-155 on ALK- ALCL tumor growth in vivo we injected 5x10^6 Mac1 cells with low (transfected with anti-miR) or high miR-155 (transfected with pre-miR) into the flanks of BALB/c mice. High miR-155 led to a significantly enhanced tumor growth and increased IL-22 in the serum, suggesting miR-155 as tumor driver and potential therapeutic target in ALK- ALCL.
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 1108. doi:1538-7445.AM2012-1108