bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3925: IGF2 activation of HER2 receptor in HER2 positive breast cancer cell lines
Authors: Helu Xousaen M. , De Leon Daisy D. 
Published: August 2012

Abstract
Breast cancer is the second leading cause of death in women. Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is detected in 20-30% of breast cancers. Overexpression of HER2 is linked to poor prognosis, more aggressive phenotype, and resistance to chemotherapy and hormonal treatment. HER2 is part of a four member family of cell surface receptors that are implicated in transmission of signals controlling cell growth and differentiation. HER2 has an intracellular domain with tyrosine kinase catalytic activity and dimerization of HER2 activates the MAP kinase and AKT pathways. HER2 receptor also heterodimerizes with the IGF1 receptor and can be activated by IGF1 receptor ligand. The insulin-like growth factor 2 (IGF2) has an important role in fetal and cancer development signaling through the insulin-like growth factor 1 receptor (IGF1R), insulin receptor (InsR), and cross-talk with the estrogen receptor alpha and beta (ERα, ERß). We hypothesized that binding of IGF-II to the IGF-1R/HER2 dimer may activate the HER2 signaling pathway. We characterized the IGF2 mRNA and protein levels in HER2 positive cell lines (BT474, SKBR3, and ZR 75-30) by qPCR and Western blot. We also analyzed the effect of IGF2 treatment on the phosphorylation levels of HER2. We measured the signaling levels of HER2 and IGF1R in the presence and absence of IGF2. Our study showed that IGF2 increases HER2 phosphorylation. Furthermore, blocking IGF1R increases HER2 protein levels. Thus, we propose that IGF2 has an important role in the activation of HER2 signaling pathway.
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 3925. doi:1538-7445.AM2012-3925
Abstract 3926: Abrogating tamoxifen resistance with the ribonucleoside analog, 8-amino adenosine
Authors: Stellrecht Christine M. , Dennison Jennifer B. , Schiff Rachel , Shentu Shujun , Gandhi Varsha 
Published: August 2012

Abstract
Hormone therapy is a prevalent treatment of choice for patients with estrogen receptor alpha (ERα) positive breast cancers. Unfortunately, due to resistance, many women do not benefit from these forms of therapy. AIB1 is a transcriptional co-activator that plays an important role in resistance to hormone therapy. Depending on the cell/gene context, agents such as tamoxifen either stimulate or antagonize the transcriptional activities of ERα. Tamoxifen binding alters ERα to an intermediate conformation with affinity for both co-activators and co-repressors, causing the conformation to be dependent on co-regulator levels in the cell milieu. The stoichiometric balance between AIB1 and co-repressors is a key determinant of tamoxifen resistance. Additionally, cross-talk between ERα and growth factor (GF) signaling further manipulates ERα activity and responsiveness to hormone therapy, particularly in cells with high AIB1 levels. Of the receptor signaling transducers, AKT, ERK, and p38 are key players in resistance. We hypothesized that strategies to target the stoichiometric balance of AIB1 to co-repressors would be clinically beneficial for abrogating tamoxifen resistance. Furthermore, it has been demonstrated that agents that are able to interfere with the ERα/GF crosstalk are also highly advantageous for abrogating resistance to tamoxifen. We have shown that the ribonucleoside analog, 8-aminoadenosine (8-NH2-Ado) is a transcription inhibitor. As such, it is expected to primarily deplete the expression of the small percentage (∼5%) of gene transcripts with short-half lives, such as AIB1. We have demonstrated that treatment of MCF-7 and BT-474 cells with non-tumoricidal concentrations of 8-NH2-Ado (1 µM) decreased AIB1 protein levels. Furthermore, using in vitro kinase assays, we demonstrated the active metabolite of 8-NH2-Ado is a selective inhibitor of MEK1, 2, and 6. An initial analysis of 4-hydroxytamoxifen dose response in two different tamoxifen resistant breast cancer cell lines, MCF-7/HER-2:18 and BT-474, demonstrated non-tumoricidal analog concentrations were able to reduce the dose of 4-hydroxytamoxifen needed to inhibit proliferation in these cells. Additionally, 8-NH2-Ado inhibited AKT and ERK1/2 activity in these cells. In conclusion, AIB1 and GF signaling molecules are attractive targets for reversing resistance to hormone therapy. Our results suggest that treating ERα positive breast cancer with combinations of tamoxifen and 8-NH2-Ado would be an effective strategy to overcome tamoxifen resistance.
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 3926. doi:1538-7445.AM2012-3926
Abstract 3928: Inhibition of the ubiquitin proteasome system differentially regulates glucocorticoid receptor-mediated transcriptional processes
Authors: Wiggins Kimberly R. , Davis Valerie , Phadke Dhiral , Shah Ruchir , Archer Trevor K. 
Published: August 2012

Abstract
The ubiquitin-proteasome system (UPS) plays an integral role in controlling protein turnover to modulate cellular processes such as growth, proliferation, differentiation, and apoptosis. This occurs through multiple mechanisms that rely on the regulation of numerous transcription factors such as steroid hormone nuclear receptors. The glucocorticoid receptor (GR) is a member of this receptor family and its activation promotes nuclear translocation and downstream transcriptional activity through the recruitment of co-regulatory complexes. Our goal is to understand the mechanisms by which the proteasome regulates glucocorticoid receptor-mediated gene transcription. To explore the effects of proteasome inhibition upon GR-mediated transcription, we used ChIP-Seq and microarray studies using breast cancer cells to examine GR binding and gene expression profiles after treatment with dexamethasone (dex) or dex in combination with a proteasome inhibitor, MG132 (dex + mg), for 1 hour and 18 hours. More than 14000 and 5000 GR-binding sites were apparent after both treatments in the 1 hour and 18 hour samples, respectively. GR binding sites seen during 1 hour of treatment can be mapped to more than 9000 genes while the binding sites in the 18 hour treatment samples mapped to over 5000 genes. In addition, over 55% of binding sites in all treatment groups are within 50 kilobases of annotated transcription start sites. To verify these putative interactions, we assayed the transcript levels of genes at both time periods and examined the levels of bound GR throughout the gene. The results reveal a differential regulation of genes that can be divided into three classes: dex-responsive, dex + mg-responsive, or dually responsive. Further analyses will reveal if there are clearly defined chromatin states that demarcate each class. These data provide insights into the intricate mechanisms of proteasome-mediated GR regulation and highlight proteasomal-regulated genes involved in numerous diseases and developmental disorders.
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 3928. doi:1538-7445.AM2012-3928
Abstract 393: Low-dose gamma-irradiation inhibits IL-6 secretion from human lung fibroblasts to suppress bronchial epithelial cell transformation by cigarette smoke carcinogen
Authors: Chen Wenshu , Xu Xiuling , Bai Lang , Padilla Mabel T. , Scott Bobby R. , Belinsky Steven A. , Lin Yong 
Published: August 2012

Abstract
The relationship between low-dose (&lt;100 mSv) ionizing radiation (LDR) and human cancer risk is controversial. While microenvironment consisting of stromal cells, cytokines and growth factors is modulated by carcinogens to favor carcinogenesis, how LDR impacts this oncogenic process is not well understood. In this study, we investigated the role and mechanism of low-dose ionizing radiation in modulating the response of human lung fibroblasts to carcinogen stimulation and the impacts of which on bronchial epithelial cell transformation. Using a human cytokine antibody array, we found that secretion of proinflammatory cytokines IL-6, CXCL1 and CXCL5 from human lung fibroblasts was induced by cigarette smoke carcinogen benzo[a]pyrene diol epoxide (BPDE), which was inhibited by a low dose of γ-ray irradiation. BPDE induced IL-6 secretion from lung fibroblasts in a dose-dependent manner, which was suppressed when the NF-κB and ERK pathways were blocked. LDR effectively inhibited NF-κB but not ERK activated by BPDE, suggesting that NF-κB is the target for LDR in fibroblasts. In addition, conditioned media from BPDE-treated fibroblasts activated STAT3 in the immortalized human bronchial epithelial cell line Beas-2B, which was blocked with an IL-6 neutralizing antibody as well as by pretreating fibroblasts with LDR. Furthermore, IL-6 significantly enhanced BPDE-induced Beas-2B cell transformation in vitro. These results suggest that LDR inhibits cigarette smoke carcinogen-induced lung carcinogenesis through suppressing secretion of protumorigenic cytokines such as IL-6 from fibroblasts in the tumor-prone microenvironment.
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 393. doi:1538-7445.AM2012-393
Abstract 3931: Progesterone and estrogen affect the expression and secretion of heparin binding epidermal growth factor like growth factor (HB-EGF) in RL95-2 cells, an endometrial cancer cell line
Authors: Otenyo Phane Gesare , Williams Ebonee , Macaulay Daniel , Carson Laura , Regisford E. Gloria C. 
Published: August 2012

Abstract
Endometrial cancer is one of the most common gynecological cancers. Heparin Binding Growth Factor-like Growth Factor exerts acute effects on cancer cells; in that it induces and promotes proliferation and hence the pathogenesis and progression of endometrial cancer. Steroid hormones directly or indirectly affect the expression of HB-EGF and may thus play a role in the malignant transformation of endometrial cells. The aim of this project is therefore to evaluate the effects of progesterone (P4) and estrogen (E2) treatments on the expression and secretion of HB-EGF in endometrial cancer cells. We hypothesized that P4 will reduce HB-EGF expression and secretion while E2 will increase its expression and secretion. To test our hypothesis, an endometrial cell line, RL95-2, was treated for four days asfollows: (1) 10−8M E2, (2)10−6M P4, (3) 10−8M E2 + 10−6M P4 (4) 10−8M E2 in two days followed by 10−6M P4 and (5) Control. Immunocytochemistry (ICC), ELISA and western blot analysis were performed to evaluate the secretion and expression of HB-EGF in RL95-2 cells. Western blot analysis and ICC showed a consistently enhanced expression of HB-EGF in cells treated with E2 and in cells treated with E2 followed by P4 relative to the control groups. Alternatively, cells treated with P4 showed a down-regulation of HB-EGF expression relative to the control group. ELISA analysis showed high secretion of HB-EGF in cells treated with E2 and cells treated with E2 followed by P4 relative to the control groups. The secretion of HB-EGF was lower in cells treated with P4 alone compared to the control. In sum, there is an acute effect of E2 and P4 on the expression and secretion of HB-EGF and thus consequently may affect endometrial cancer cell proliferation.
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 3931. doi:1538-7445.AM2012-3931
Abstract 3932: IL13Rα2 regulates cell invasion, and is a therapeutic target for adrenocortical carcinoma
Authors: Jain Meenu , Zhang Lisa , Joshi Bharat , Puri Raj , He Mei , Kebebew Electron 
Published: August 2012

Abstract
Adrencortical neoplasms are one of the most common human neopolasms. Furthermore, it is difficult to distinguish localized benign from malignant adrenal tumors. Adrenocortical carcinoma (ACC) is a relatively rare but aggressive malignancy with limited therapeutic options for patients with advanced and metastatic disease. Several genome wide expression studies have shown overexpression of Interleukin-13 Receptor alpha2 (IL13Rα2) in some human malignancies but the function of this gene in cancer cells is poorly understood. We evaluated IL13Rα2 mRNA expression in normal (n=21), and in benign (n=78) and malignant (n=10) adrenocortical tumors. We found 11-fold higher expression in malignant tumors compared to benign (p&lt;0.05) and absent expression in normal adrenocortical tissue. Immunohistochemistry analysis confirmed high protein expression in malignant and benign tumors and absent expression in normal adrenocortical tissues (p&lt;0.05). IL13Rα2 mRNA expression level also had 90% accuracy for distinguishing benign from malignant adrenocortical tumors. We used IL13Rα2 siRNA knockdown to assess its effect on cell proliferation and cell invasion in the NCI H295R cell line, which expressed high levels of IL13Rα2. IL13Rα2 knockdown did not significantly affect cell proliferation but did decrease invasion by 60% as compared to negative control (p&lt;0.05). To determine the significance of IL13Rα2 as a therapeutic target for ACC, we evaluated the sensitivity in two ACC cell lines (NCI-H295R with high IL13Rα2 expression and SW13 with low IL13Rα2 expression) to a highly specific IL-13 targeting immunotoxin (IL-13-PE). We found the IC50 for IL-13-PE was 1.3ng/ml (NCI-H295R) and 1000ng/ml (SW13) in the cell lines. Based on this observation, we then tested the efficacy of IL-13-PE therapy in an ACC xenograft model in athymic nude mice. Mice receiving either intratumoral or intraperitoneal IL-13-PE therapy as compared to control showed a significant reduction in tumor size as well as tumor necrosis (p&lt;0.05), and had prolonged survival (p&lt;0.05). Both routes of IL-13-PE administration were well tolerated with no significant toxicity. Our study indicates that IL13Rα2 is overexpressed in 100% of ACC, is a good diagnostic marker for ACC, regulates ACC cell invasion, and is a novel therapeutic target for the treatment of ACC.
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 3932. doi:1538-7445.AM2012-3932
Abstract 3934: HCV core protein upregulates the expression of vascular endothelial growth factor via the nuclear factor-α/hypoxia-inducible factor-1α axis under hypoxic conditions
Authors: Abe Mitsuhiko , Koga Hironori , Yoshida Takafumi , Masuda Hiroshi , Iwamoto Hideki , Sakata Masahiro , Hanada Shinichiro , Nakamura Toru , Taniguchi Eitaro , Kawaguchi Takumi , Yano Hirohisa , Torimura Takuji , Ueno Takato , Sata Michio 
Published: August 2012

Abstract
Aim: Hepatitis C virus (HCV) core protein critically contributes to hepatocarcinogenesis, which is often observed in liver cirrhosis. Since the liver cirrhosis microenvironment is affected by hypoxia, we focused on the possible driving force of HCV core protein on signal relay from hypoxia-inducible factor (HIF)-1α to vascular endothelial growth factor (VEGF). Methods: Human hepatocellular carcinoma cells stably overexpressing HCV core (Core cells) and NS5A (NS5A cells) were established; empty vector-transfected (EV) cells were used as controls. Hypoxia was induced by oxygen deprivation or by using cobalt chloride (CoCl2). YC-1 was used to inhibit HIF-1α expression. Protein analyses for cultured cells and liver tissues obtained from CoCl2-treated HCV core-transgenic (Core-Tg) mice were performed by Western blot and/or immunocytochemistry. Cellular mRNA levels were evaluated by quantitative real-time RT-PCR. Results: Under hypoxia, the sustained expression of HIF-1α, but not HIF-2α, was profoundly observed in Core cells but, was faint in EV and NS5A cells. Immunocytochemistry revealed increased HIF-1α in the nucleus. HIF-1α mRNA levels were significantly higher in Core cells than in EV cells under both normoxia and hypoxia. The HIF-1α-targeted VEGF and Bcl-xL expressions were increased in Core cells under hypoxia and abolished by YC-1 treatment. Hypoxic liver samples of Core-Tg mice indicated significant increases in both HIF-1α and VEGF expression compared to the wild type. Conclusions: HCV core protein has the distinct potential to transcriptionally upregulate and sustain HIF-1α expression under hypoxia, thereby contributing to increased VEGF expression, a key regulator in the hypoxic milieu of liver cirrhosis.
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 3934. doi:1538-7445.AM2012-3934
Abstract 3940: Activation of Signal Transducer and Activator of Transcription 3 (STAT3) in ovarian cancer: The hypoxic implications
Authors: McCann Georgia A. , Naidu Shan , Tierney Brent J. , Sudhakar Meryl , Cohn David E. , Selvendiran Karuppaiyah 
Published: August 2012

Abstract
Background: The hypoxic microenvironment plays a key role in tumorigenesis and the development of therapeutic resistance in epithelial ovarian cancer (EOC). The goal of this study was to examine the expression of STAT3 in hypoxic EOC, to understand its mechanism of activation, and to explore the therapeutic efficacy of a novel compound HO-3867. Methods: Expression of STAT family proteins in cell lines and human tumor specimens was analyzed via western blot and IHC. MTT was used to assess cell viability and apoptotic analysis was performed using flow cytometry. Over-expression or suppression experiments were performed using S1PR1 cDNA and shRNA. Tumor xenografts were made with cell lines exposed to hypoxic preconditioning. Results: pSTAT3 Tyr705 is highly expressed in ovarian cancer cell lines exposed to hypoxia as well as in hypoxic regions of advanced human EOC tumor specimens. Accelerated xenograft tumor growth was observed when implanted cells were pre-conditioned in a hypoxic microenvironment. Similar to our in vitro findings, the tumor xenografts of hypoxic ovarian cancer cells (HOCCs) had high expression of pSTAT3 and its target proteins. We found an increased expression of sphingosine-1-phosphate receptor 1(S1PR1) in HOCCs, a known positive feedback regulator of STAT3 transcription. Suppression of S1PR1 expression with shRNA significantly reduced the expression of pSTAT3 Tyr705 through the inhibition of the JAK kinases, resulting in decreased cell survival. Conversely, overexpression of S1PR1 with cDNA increased pSTAT3 Tyr705 and promoted cell proliferation under hypoxic conditions. Finally, treatment of HOCCs with the novel synthetic compound HO-3867 resulted in decreased expression of pSTAT3 Tyr705, as well as STAT3-regulated proteins VEGF, Bcl-xL, Bcl-2, and cyclin D1. The rapid downregulation of pSTAT3 Tyr705 was associated with accelerated ubiquitin-dependent degradation. An induction of apoptosis contributed to inhibition of cell proliferation as HO-3867-exposed cells exhibited elevated levels of cleaved caspases and PARP. Conclusions: The hypoxic microenvironment results in STAT3 activation as evidenced in our in vitro and in vivo models. S1PR1 is involved in STAT3 Tyr705 activation in hypoxic ovarian cancer via the JAK signaling pathway. The specific targeting of hypoxia-induced tyrosine phosphorylation of STAT3 with HO-3867 is a novel therapeutic strategy in the treatment of hypoxia-mediated chemotherapeutic resistant 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 3940. doi:1538-7445.AM2012-3940
Abstract 3945: HIFs regulate alternative splicing of HIF target genes
Authors: Sena Johnny , Wang Liyi , Hu Cheng-jun 
Published: August 2012

Abstract
Alternative splicing is the process in which identical pre-mRNA molecules are spliced in different ways, allowing individual gene to express multiple mRNAs or isoforms that encode proteins with diverse and even antagonistic functions. Alternative splicing occurs in over 70% of human genes, is important in normal development and many diseases including cancer. It is well known that most solid-tumors are hypoxic and the hypoxic microenvironment is a driving force for tumor progression and metastasis by hypoxia-inducible-factor (HIF)-mediated transcriptional programs that increase genes involved in tumor growth, angiogenesis, and metastasis. Here, we report a novel finding that transcriptional factor HIF not only activates gene expression, also regulates RNA splicing of its target genes, generating isoforms that favor tumor growth. Using an Exon Microarray we found that approximately 1000 genes are predicted to undergo hypoxia-mediated AS in Hep3B cells, 100 of those genes are hypoxia inducible genes. Using RT-PCR, RT-qPCR and WB we validated that the first 10 HIF target genes, CA9, ANGPTL4, WNK1, PLOD2, ADM, DUOX2, ENO2, P4HA2, EGLN3, and PDK1 undergo hypoxia-mediate AS, as predicted by exon array. Interestingly, AS of these genes is regulated by HIFs, not by hypoxia since: 1) siRNA knockdown of ARNT, HIF1, or HIF2 inhibits hypoxic induction of HIF target genes as well as inhibits hypoxia-mediated splicing changes; and 2) Normoxic HIF activity by deleting VHL, inhibiting PHD, or expressing normoxic-stable HIF protein led to hypoxic splicing patterns of HIF target genes, demonstrating HIF activity is sufficient to induce alternative splicing of HIF target genes. However, AS of HIF target genes cannot be explained by increased transcription of these genes since no splicing changes were observed when these genes were activated by hybrid protein with HIF transactivation domains replaced by VP16, E2F1, or SP1 transactivation domain. Further experiments indicated that the N-terminal transactivation domains (N-TAD) of HIF1α or HIF2α are responsible for splicing changes of these HIF-target genes. In summary, we have uncovered a novel function of HIFs in the regulation of target gene splicing. The discovery of HIF's role in mRNA splicing of its target genes will change the dogma concerning the role of HIF in cancer progression. We propose that HIFs promote cancer progression not only through transcription activation but also through alteration of mRNA splicing of HIF targets. RO1 CA134687 NIH/NCI (Hu)
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 3945. doi:1538-7445.AM2012-3945