bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5130: Integrative approaches for the identification of therapeutic targets in basal like breast cancer from multi-level molecular data
Authors: Tesson Bruno M. , Rigaill Guillem , Vincent-Salomon Anne , Gentien David , Roman-Roman Sergio , Pierré Alain , Cruzalegui Francisco , Depil Stéphane , Tucker Gordon , Dubois Thierry , Barillot Emmanuel 
Published: August 2012

Abstract
Basal-like breast cancer is a molecular subtype of breast carcinoma accounting for up to 15% of cases and associated with a poor prognosis. There is no targeted therapy for this disease; since most basal-like breast cancers do not over-express HER2 and are negative for hormone receptors, they cannot be treated with trastuzumab antibody (anti-HER2) or anti-hormonal therapies. Finding therapeutic targets for the treatment of basal-like tumors is therefore a priority in breast cancer research. In this project, biopsies for the different subclasses of breast cancer (46 basal-like, 33 HER2+/ER-, 35 luminal A and 40 luminal B) were obtained from the Biological Center of Institut Curie and characterized by immuno-histochemistry. Using different microarray platforms, genome-wide profiles were obtained at the DNA, messenger RNA, and microRNA levels. Additionally, data were collected for a selection of 150 proteins using Reverse Phase Protein Arrays. We present the results of separate analyses of each of these molecular levels, and we introduce methods that integrate information across multiple layers of data to pinpoint potential drivers of the disease. In particular, we propose an approach to identify genome regions where copy number alterations correlate with transcriptome-wide perturbation of gene expression. Such correlation suggests that these regions may harbor genes playing an important role in carcinogenesis. Using criterions based on co-expression and on prior biological knowledge, the method determines the genes in these regions that are most likely to be cancer drivers and may therefore be relevant as therapeutic targets. Using HER2+ tumors to illustrate the approach, we show that the method is indeed able to designate the HER2 oncogene as a likely driver. With the addition of miRNA and protein data to these integrated studies, we hope that such approaches will suggest putative cancer driving genes as novel potential therapeutic targets.
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 5130. doi:1538-7445.AM2012-5130
Abstract 5140: The functional c-Myc dependent polymorphisms of telomerase promoter control hTERT expression and are associated with telomere length
Authors: Woong Son Ji , Choi Yi Young , Park Jae Yong , Jeon Hyo-Sung 
Published: August 2012

Abstract
Telomere shorting occurs after repeated cell division and has a key role in cell senescence, differentiation, and immortalization. Thus, telomere maintenance is critical for cancer progression. Telomere length is mainly regulated by telomerase activity associated with transcriptional activity of human telomerase reverse transcriptase (hTERT), a subunit of telomerase. The dysregulation and reactivation of hTERT gene expression may play an important role in facilitating tumor development. The hTERT promoter region was well identified and is rich in transcription factor binding sites including c-myc, SP1, and esterogen. In our previous study, hTERT polymorphisms, rs2753940 (-1327C&gt;T), rs2853669(-244 T&gt;C), rs2736100 and MNS16A, were examined for lung cancer association study. To identity effect of the hTERT polymorphisms on telomere length and transcriptional activity, we determined telomere length according to hTERT polymorphisms. The two hTERT polymorphisms, rs2753940 (-1327C&gt;T), rs2853669 (-244 T&gt;C), have a significant association with telomere length (P = 0.04, P = 0.013, respectively). This telomere length may be determined by hTERT expression which was regulated promoter polymorphism (rs2853669) by changing of c-MYC binding. We evaluated that rs2853669 is significantly associated with lung cancer prognosis in NSCLCs. Two promoter SNPs have a role in expression of hTERT, which may affect telomere length. These two polymorphisms may be used for risk and prognostic marker of lung 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 5140. doi:1538-7445.AM2012-5140
Abstract 5154: Fatty acids mediated regulation of cancer metabolism
Authors: Rizi Bahar Salimian , Nagrath Deepak 
Published: August 2012

Abstract
Although fatty acids have been shown to modulate progression, growth and invasiveness of cancer cells, it remains unclear how saturated and unsaturated fatty acids affect metabolic reprogramming of aggressive and nonaggressive cancer metabolism. In this study, we tested the hypothesis that fatty acids induce differential competitive effects on glucose oxidation in aggressive and nonaggressive ovarian cancer cells. Normal cells rely mainly on mitochondrial oxidative phosphorylation for their required energy supply, however, cancer cells utilize aerobic glycolysis pathway for their energetic need. We hypothesized that high fat diet could deregulate this metabolic alteration in cancer cells. Such as glucose, fatty acids are an influential source of ATP, energy currency, within a cell. In our study, using metabolic footprinting we studied the affect of both saturated (stearic and palmitic acid) and unsaturated fatty acids (linoleic and oleic) on glycolysis, pentose phosphate pathway and TCA cycle. Moreover, we also studied the effect of glucose on fatty acid oxidation, uptake and endogenous fatty acid synthesis. Metabolic flux analysis was done for comparative metabolic profiling under various nutritional conditions. We observed that fatty acids differentially regulate highly invasive ovarian cancer (SKOV3 and SKOV3ip) cells than less invasive ovarian cancer (OVCAR3) cells. Interestingly, we found strong effect of fatty acids on glycolysis in less invasive cancer cells. In contrast, our study showed that glucose has dominant effect on aggressive cells compared to less aggressive cells. Our studies emphasize the role of fatty acids in ovarian cancer growth, invasion and migration and underlie the need to develop therapy based on high fat diet synergistically with existing chemotherapeutics and cancer drugs.
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 5154. doi:1538-7445.AM2012-5154
Abstract 5174: Novel signaling interactions of type XV collagen: Implications for tumor suppression
Authors: Clementz Anthony G. , Mutolo Michael J. , Harris Ann 
Published: August 2012

Abstract
Most clinical therapeutics used to date depend on specific targeting of cellular components to treat cancers. However, the environment outside the tumor cell is also critical since it may provide new targets to treat malignant and resistant cancers, independent of the tumor. We aim to advance the understanding of the early stages of cancer, prior to metastasis by determining the role of a non-fibrillar collagen (Type XV) and its interactions with the tumor stroma and extracellular environment. Type XV collagen (COLXV) is found in basement membrane zones where it assumes a pretzel-like structure but unlike the majority of fibrillar collagens does not form tight lattice networks surrounding the cell. Loss of COLXV during progression of aggressive cancers (including breast, pancreas, and ovarian carcinomas and melanomas) precedes basement membrane invasion and metastasis. Moreover, the loss of COLXV from the distal side of basement membrane zones and the resulting deficit in its interactions with other proteins may determine its specific function in tumor progression and eventual metastasis. In this context we have identified critical collagen-binding cell surface receptors on the tumor cell, which interact with COLXV and appear to mediate its functions. These receptors have also been reported to show altered signaling in cancer. We previously showed that over-expression of COLXV in cervical cancer cells alters the growth properties of these cells both in vitro and in vivo, and showed that type XV collagen is a dose-dependent suppressor of tumorigenicity in vivo. We now show that over-expression of COLXV inhibits epithelial to mesenchymal transition (EMT) in vitro and has a dramatic effect on the associated signaling events. We are now further investigating the mechanisms of tumor/stroma crosstalk that are impacted by COLXV and subsequently by its depletion.
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 5174. doi:1538-7445.AM2012-5174
Abstract 5268: Standardized and validated ATCC breast cancer panels: A tool for the rapid validation of biological hypotheses.
Authors: Zhang Chengkang (CK) , Elias-Bachrach Michal , Challberg Sherry , Bettoun David 
Published: August 2012

Abstract
Advances in personalized medicine rely on knowledge of validated markers that predict response to treatment. The availability of such information could significantly impact preclinical drug optimization and reduce the cost of clinical trials. Conversely, improving drug efficacy based on clinical data requires performing studies in defined biological systems. These defined systems typically are clonal cell lines, which have been key in advancing our understanding of numerous disease states, including cancer. A number of recent comprehensive studies have demonstrated that individual cell lines are restricted along discreet lineages and therefore do not recapitulate tumor heterogeneity observed in patients However, the use of a combination of such cell lines reflected the clinical diversity observed in patient. (Neve et al, 2006; Kao J et al, 2006; Keller PJ et al 2010). We postulated that the use of carefully characterized cell lines combined into biologically relevant panels might provide valuable insights into studies on target validation, lead optimization, mechanisms of action and evaluation of efficacy in various patient subgroups. The lack of uniform culture conditions among various tumor cell lines hampers the design and conduct of experiments using such cell line panels and complicates the interpretation of the results obtained from them. We therefore undertook to combine panels of breast cancer cell lines that represented major clinical manifestations of the disease and culture them under standardized conditions. We were able to establish culture conditions that maintained the expression of mRNA and cell surface proteins for validated therapeutic and clinical markers. Using a small collection of clinically validated and investigational compounds we provide several example about how carefully selected and characterized cell panels can be used to carry out pharmacology studies and address questions pertinent to tumor biology and anti-cancer drug development.
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 5268. doi:1538-7445.AM2012-5268
Abstract 5277: MMP-2 suppression abrogates irradiation-induced microtubule formation in endothelial cells by inhibiting αvβ3-mediated SDF-1/CXCR4 signaling
Authors: Maddirela Dilip , Kesanakurti Divya , Chetty Chandramu , Dinh Dzung H. , Rao Jasti S. 
Published: August 2012

Abstract
The majority of glioblastoma multiforme (GBM) tumors recur after the radiation (IR) treatment by increasing angiogenesis and IR-induced signaling events in endothelial cells that are involved in tumor neovascularization; these signaling events have yet to be well characterized. We observed that IR (8 Gy) significantly elevated MMP-2 expression and gelatinolytic activity in 4910 and 5310 human GBM xenograft cells. In addition, endothelial cells treated with tumor conditioned media (CM) obtained from IR-treated 4910 and 5310 cells showed increased microtubule formation. Thus, we investigated the possible anti-angiogenic effects of MMP-2 downregulation using siRNA (pMMP-2.si) in IR-treated cells and further determined the effect of CM obtained from mock, pSV (scrambled vector) and pMMP-2.si on endothelial cell growth and vessel formation. pMMP-2.si-CM-treated endothelial cells showed inhibited IR-CM-induced αvβ3, SDF-1, CXCR4, phospho-PI3K and phospho-AKT expression levels. In vitro angiogenesis assay showed that the pMMP-2.si+IR decreased the IR-induced vessel formation in endothelial cells. Immunofluorescence and immunoprecipitation experiments indicated the abrogation of αvβ3-SDF1 interaction in pMMP-2.si-CM-treated endothelial cells when compared to mock or pSV treatments. External supplementation of either rhMMP-2 or rhSDF-1 counteracted and noticeably reversed the pMMP-2.si-inhibited SDF-1, CXCR4, phospho-PI3K and phospho-AKT expression levels and angiogenesis, thereby confirming the role of MMP-2 in the regulation of αvβ3-mediated SDF-1/CXCR4 signaling. In corroboration with the in vitro results, the in vivo mouse dorsal air sac model also showed reduced angiogenesis with the injection of pMMP-2.si-treated xenograft cells whereas injection of mock or pSV-treated cells resulted in robust formation of characteristic neovascularization. Collectively, our data indicate the role of MMP-2 in the regulation of SDF-1/CXCR4 signaling-mediated angiogenesis in endothelial cells and demonstrates the anti-angiogenic efficacy of combining MMP-2 downregulation and IR when treating GBM in the future.
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 5277. doi:1538-7445.AM2012-5277
Abstract 5278: Suppression of angiogenic potential of breast cancer by the inhibition of SAF-1 transcription factor activity
Authors: Ray Alpana , Dhar Srijita , Ray Bimal K. 
Published: August 2012

Abstract
Angiogenesis plays an important role in the tumor growth and metastasis by facilitating increased blood supply and thus fueling unwanted growth factors and nutrients to the growing tumor. Vascular endothelial growth factor (VEGF) is recognized as a multifunctional angiogenic stimulator that stimulates blood vessel formation and endothelial cell survival. Recent therapeutic trials with anti-VEGF antibody bevacizumab (Avastin), although produced beneficial effects on some cancers including colorectal and lung cancers, had very limited beneficial outcome in breast cancer. The diverse response of avastin raised questions about the efficacy of anti-VEGF antibody approach for breast cancer therapy. Despite the disappointing outcome, it cannot be ignored that regulation of angiogenesis plays a critical role in breast cancer. We hypothesized that angiogenesis may be better controlled by blocking the synthesis of VEGF protein as opposed to the present approach that attempts to block the functions of VEGF by using antibodies. Induction of VEGF by a plethora of physiological and environmental stimuli strongly suggests the presence of multiple routes of VEGF synthesis, which are incompletely understood. We present evidence for a novel mode of transcriptional induction of VEGF, regulated by an inflammation-responsive transcription factor, SAF-1. Incidentally, inflammatory breast cancer exhibits increased angiogenesis and has a higher metastatic potential than noninflammatory breast cancer, supporting the notion that chronic inflammation plays a strong role in angiogenesis and in the progression of cancer. SAF-1 is present in high abundance in human breast cancer tissues. We show that inhibition of endogenous SAF-1 by antisense shRNA can markedly inhibit VEGF expression and block cancer cell-supported vascular endothelial cell function and angiogenesis. Furthermore, SAF-1 inhibition by shRNA reduces tumor growth in mouse tumor model. We provide evidence that SAF-1-mediated induction of VEGF remains suppressed by KLF-4 transcription factor which is abundantly present in normal breast epithelial cells but absent in breast cancer cells. Mutually exclusive interaction of KLF-4 and SAF-1 at the VEGF promoter provides a mechanism for regulation of low-expression of VEGF in normal breast tissues. In correlation, lack of KLF-4 in breast cancer cells appears to be linked to un-restricted interaction of SAF-1 leading to the induction of VEGF expression. Together, our studies provide a new insight into the molecular mechanisms of VEGF expression regulated by SAF-1 and its impact in angiogenesis.
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 5278. doi:1538-7445.AM2012-5278
Abstract 5284: EMMPRIN mediates VEGF activation of VEGFR-2 in melanoma cells
Authors: Khayati Farah , Mourah Samia 
Published: August 2012

Abstract
EMMPRIN's expression in melanoma tissue was reported to be predictive of poor prognosis. Here we demonstrate that EMMPRIN up-regulated VEGF receptor-2 (VEGFR-2) in two different primary melanoma cell lines and consequently increased migration and proliferation of these cells while inhibiting their apoptosis. SiRNA inhibition of VEGFR-2 expression abrogated these EMMPRIN effects. EMMPRIN regulation of VEGFR-2 was mediated through the over-expression of HIF-2α and its translocation to the nucleus where it forms heterodimers with HIF-1β. These results were supported by an in vivo correlation between the expression of EMMPRIN with that of VEGFR-2 in human melanoma tissues as well as with the extent of HIF-2α localization in the nucleus. They demonstrate a novel mechanism by which EMMPRIN promotes tumor progression through HIF-2α/VEGFR-2 mediated mechanism, with an autocrine role in melanoma cell malignancy. As VEGF/VEGFR2 system has been implicated in regulation of melanoma cells migration, proliferation and apoptosis, the role of EMMPRIN in the regulation of these cellular properties was investigated. Blocking EMMPRIN by siRNA have shown that VEGF enhancement of melanoma cell migration requires EMMPRIN. The inhibition of EMMPRIN in cancer may thus simultaneously target both the VEGFR-2/VEGF system and the matrix degrading proteases to block tumor cell growth and 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 5284. doi:1538-7445.AM2012-5284
Abstract 529: Impaired NF-κB signaling in myeloid cells enhances urethane-induced lung carcinogenesis
Authors: McLoed Allyson G. , Zaynagetdinov Rinat , Sherrill Taylor , Yull Fiona E. , Blackwell Timothy S. 
Published: August 2012

Abstract
Nuclear Factor κB (NF-κB) regulates airway inflammation and has been implicated in lung tumorigenesis. We and others have previously described a pro-tumorigenic role for NF-κB activity in airway epithelial cells. However, the role of NF-κB signaling in other cell types, including myeloid cells, in modulation of lung tumorigenesis is unknown. The goal of these studies is to determine the role of myeloid cell-specific NF-κB in lung tumorigenesis. In mice with myeloid cell-targeted IKKβ deletion (IKKβΔmye mice), we observed increased inflammatory mediator expression at 1 week after intraperitoneal injection of urethane (1 μg/g). At 6 weeks post-urethane injection, lungs of IKKβΔmye mice exhibited an increased atypical adenomatous hyperplastic lesion burden, which was accompanied by an increased inflammatory cell influx into the lungs of IKKβΔmye mice compared to wild-type (WT) controls. No difference in total macrophages or the proportion of M2 polarized macrophages in whole lungs was observed by flow cytometry at 6 weeks post-urethane; however, the proportion of CD11b+Gr1hi cells was increased in IKKβΔmye mice. At 4 months after urethane injection, we found an increase in lung tumor numbers (5.6±0.6 in WT, 10.0±1.5 in IKKβΔmye) and a trend towards decreased tumor size in IKKβΔmye mice compared to WT controls. IKKβΔmye mice contained significantly higher numbers of neutrophils in bronchoalveolar lavage at this time point compared to WT controls. In addition, lungs of IKKβΔmye mice exhibited more CD11b+Gr1hi cells in whole lungs as measured by flow cytometry. Our data indicate that inhibition of NF-κB signaling in myeloid cells results in a paradoxical increase in lung inflammation accompanied by enhanced urethane-induced lung tumorigenesis. We conclude that the impact of NF-κB signaling on lung tumorigenesis is cell type specific and that NF-κB activation in myeloid cells functions to limit urethane-induced inflammation and reduce tumor formation in the lungs.
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 529. doi:1538-7445.AM2012-529
Abstract 5294: Increased angiogenesis resulting from TIMP-1 inhibition of TSP-1 is mediated by PI3kinase and FAK interactions
Authors: Ohja Juhi , Gayatri Sitaram , Nalluri Srilatha , Rojiani Amyn M. , Rojiani Mumtaz V. 
Published: August 2012

Abstract
Tissue Inhibitor of Matrix Metalloprotease -1 (TIMP-1), one of the four natural inhibitors of matrix metalloproteinases was initially identified for its Erythroid Potentiating Activity. Since then, it has been shown to independently induce cell proliferation and inhibit apoptosis in a number of cell types. TIMP-1 has also been shown to promote, but also more often to inhibit angiogenesis. Previously, we have shown that TIMP-1 overexpression in a lung adenocarcinoma cell line (H2009) resulted in more aggressive and vascular tumors in nude mice and increased capillary network formation and tumorigenicity in vitro. An angiogenesis pathway-specific gene array had identified a 3-fold reduction in thrombospondin 1 (TSP-1) levels in the TIMP-1 overexpressing clone HB-1. TSP-1 siRNA clone exhibited a similar increase in in vitro angiogenesis assays. In the present study, we have sought to identify the signaling pathway involved whereby TIMP-1 inhibits TSP-1. To this end, we have used specific inhibitors to inhibit TIMP1 initiated signaling pathways. MAP kinase, PI3/Akt inhibitors were used, either singly or in combination with Focal Adhesion kinase (FAK) inhibitor. Our results indicate a synergistic interaction between PI3/Akt pathway and FAK signaling, which restores TSP-1 levels by approximately 3-fold relative to control. Gelatin zymography of serum-free conditioned media (SFCM) revealed a reduction in proMMP-9 level in the HB-1 clone versus H2009. Additionally MMP9 specific ELISA reveals a two-fold reduction in MMP9 levels. This is in tune with the role of TSP-1 as an inhibitor of MMP-9 activation such that decreased TSP-1 level results in increased activation of MMP-9 with a concomitant reduction in the extracellular level of proMMP-9. Thus our findings define interaction of TIMP-1 via PI3kinase and FAK signaling. resulting in TSP-1 decrease and subsequent downstream promotion of angiogenesis with increased tumor kinetics.
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 5294. doi:1538-7445.AM2012-5294