bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1021: HDM2 inhibition augments the antitumor and antiangiogenic effects of sunitinib by suppressing sunitinib-induced SDF-1 expression and tumor recruitment of CD11b/Gr1+ MDSC in RCC xenografts
Authors: Panka David J. , Liu Qinjun , Signoretti Sabina , Mier James W. 
Published: August 2012

Abstract
The VEGFR2 inhibitor sunitinib induces transient growth arrest of 786-0 RCC xenografts during which p53 as well as several p53-dependent genes (e.g. p21, HDM2, and collagen prolyl hydroxylase) are induced. Within a short period of time tumor growth resumes despite continued administration of the sunitinib. However, the development of resistance to sunitinib is associated with continued expression of p53 but the loss of p53 transcriptional activity as determined by the suppressed expression of the above target genes and the increased expression of the p53 transcriptional inhibitor hdmx. Recently, several small molecule antagonists of the p53 negative regulator hdm2 have been developed which stabilize p53 expression. One of these, MI-319 (Sanofi-Aventis), in addition to inhibiting hdm2 also inhibits hdmx. We have combined MI-319 with sunitinib in two separate xenograft model of RCC resistance. The addition of MI-319 prevents the development of resistance to sunitinib. The enhanced antitumor activity of the drug combination is associated with enhanced suppression of the vasculature and increased evidence of apoptosis relative to sunitinib alone. The addition of MI-319 to sunitinib reestablishes p53 activity in 786-0 and A498 xenografts as determined by p21 and hdm2 expression. Furthermore, whereas sunitinib alone results in increased expression of SDF-1 and the recruitment of CD11b, GR-1 myeloid suppressor cells, the addition of MI-319 to the sunitinib decreases expression of SDF-1 and suppresses the recruitment of the myeloid suppressor 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 1021. doi:1538-7445.AM2012-1021
Abstract 1047: Suppression of the chromatin remodeling protein CHD3 and platinum resistance in ovarian cancer
Authors: Cutter Noelle , Vigliotti Michele , Lum Elena , Wrzeszczynski Kazimierz O. , Varadan Vinay , Dimitrova Nevenka , Levine Douglas A. , Lucito Robert 
Published: August 2012

Abstract
Epithelial ovarian cancer is the leading cause of death from gynecological malignancies. Currently platinum-based chemotherapy, coupled with a taxane based drug is the primary treatment for ovarian cancer. Approximately 25% of patients either present with or rapidly develop resistance to platinum based chemotherapy and all recurrent tumors ultimately become resistant. Epigenetic modifications have been associated with tumor formation and progression and may contribute to therapy response. We hypothesize that Epigenetic changes such as DNA CpG methylation is in part responsible for the onset of chemoresistance of EOC. To identify epigenetically regulated genes associated with ovarian cancer chemotherapy resistance, a genome wide approach was used. For the most significant genes an in vitro culture system was developed to study platinum resistance. Candidate genes were screened by addition of shRNAs to model the transcriptional suppression caused by DNA methylation and genes that scored positive for increasing resistance were identified, one of them being the CHD3 gene. Here we show that loss of expression of CHD3, a member of the Mi-2/NuRD complex, causes increased resistance to platinum chemotherapy drugs. Additionally, ovarian cell lines transcriptionally silenced for CHD3 are more invasive, and have increased migratory ability. Recent evidence suggests molecular and phenotypic associations between chemo resistance and the acquisition of epithelial-mesenchymal transition of cancer cells. The transition of epithelial cell to a mesenchymal cell requires an alteration in morphology, cellular architecture, adhesion, and migration capacity. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. Our results indicate that when CHD3 is silenced, cells undergo an EMT-like transition thereby allowing them to bypass apoptosis and resist platinum based therapy. Taken together, we provide the first evidence of a role for CHD3 as an important epigenetic regulator of chemoresistance in ovarian cancer and hypothesize EMT as one of the underlying mechanisms. Furthermore, CHD3 expression might represent a therapy response predictor and could be a future therapeutic target for 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 1047. doi:1538-7445.AM2012-1047
Abstract 1053: DNMT3B7 alters E-cadherin expression and cell proliferation in breast cancer cells
Authors: Brambert Patrick R. , Rehbein Jennifer , Slezak Izabela , Kelpsch Daniel J. , Ostler Kelly R. , Godley Lucy A. , Raimondi Stacey L. 
Published: August 2012

Abstract
Breast cancer is the second-leading cause of cancer death among women in the United States and the progression from non-invasive to invasive/metastatic disease correlates with an increased risk of death. Changes in DNA methylation have been shown to be important in breast cancers. However, the mechanism by which cancer cells acquire and maintain abnormal methylation is not well understood. DNA methyltransferases (DNMTs) are responsible for monitoring and altering DNA methylation patterns in cells. Interestingly, we have identified many aberrant DNMT3B transcripts in cancer cells compared to normal cells. Therefore, we hypothesize that aberrant DNMT3B isoforms alter gene and protein expression to promote tumor progression in breast cancer cells. Our studies indicate that the breast cancer cell lines MCF-7 and MDA-MB-231 express many aberrant DNMT3B isoforms including DNMT3B7 and ΔDNMT3B6. Interestingly, the invasive MDA-MB-231 cells express increased levels of DNMT3B7 and ΔDNMT3B6 compared to the poorly invasive MCF-7 cells. To further our studies, poorly invasive MCF-7 cells were stably transfected with a DNMT3B7 expression construct to determine the role of this aberrant transcript in tumor progression. Preliminary data indicate that the increased expression of DNMT3B7 in these cells correlates with a significant increase in growth. Specifically, cells expressing more DNMT3B7 grow faster than those with lower levels of the aberrant protein. Furthermore, E-cadherin expression is inversely correlated with DNMT3B7 expression indicating that the expression of this aberrant protein may lead to a more aggressive phenotype. Finally, soft agar assays have been performed to determine the functional significance of these findings. The novel results presented in this study suggest the need for additional studies to determine the role of aberrant DNMT3B transcripts in cancer. Ultimately, this work may lead to a better understanding of breast cancer progression and the development of novel 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 1053. doi:1538-7445.AM2012-1053
Abstract 1054: The role of DNMT1 in the DNA damage response
Authors: Lee Gun Eui , Robertson Keith D. 
Published: August 2012

Abstract
DNA methyltransferases (DNMTs) are proteins reponsible for establishing and maintaining genome-wide patterns of DNA methylation, an epigenetic signature regulating gene expression and genome integrity. DNMT1 is regarded as the maintenance enzyme while DNMT3A/3B are involved in the de novo synthesis of DNA methylation pattern. Besides its known role in copying methylation during replication, DNMT1 has been reported to be involved in the DNA damage response by recruitment to damaged sites on DNA. However, the mechanism of how DNMT1 takes part in DNA damage repair (DDR) remains to be elucidated. Our previous study showed that DNMT1 is an early responder to DNA double-strand breaks and interacts with components of the DDR machinery (Ha, KS et al, 2011, Hum. Mol. Genet., 20 (1): 126-140). In order to further characterize the role of DNMT1 in DDR, we analyzed DNMT1 in cis and trans. In our previous study, we observed that DNMT1 is recruited to DNA damage sites rapidly and transiently. Since DNMT1 is present throughout the cell cycle, this rapid and transient localization suggests that, upon DNA damage, in order to localize on DNA damage sites, a fraction of the DNMT1 protein pool might be modified and/or its complement of binding partners transiently altered. To this end, we purified DNMT1 from mammalian cells before and after ionizing radiation and analyzed its post-translational modifications (PTMs) by mass spectrometry. DNMT1 shows multiple unique patterns of PTMs including acetylation and methylation before and after ionizing radiation. In order to characterize trans-acting partners of DNMT1 after DNA damage, we purified DNMT1 complexes after protein cross-linking and used mass spectrometry to determine the identity of interacting factors. Consistent with changes in the localization and PTM patterns on DNMT1 in the presence and absence of DNA damage, several known and novel DNMT1-protein interactions are also altered in cells with damaged DNA. Finally, in order to understand the role of DNMT1 in the DDR mechanism in a physiological context, we used siRNA to acutely reduce levels of DNMT1 in the presence and absence of DNA damage. Knock-down of DNMT1 reduced the activation of DDR signaling molecules such as ATM, CHK1, and γ-H2AX in a colon cancer cell line. Collectively, our results demonstrate that DNMT1 is a critical molecule involved in coordinating DNA damage signaling with DNA repair mechanisms.
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 1054. doi:1538-7445.AM2012-1054
Abstract 1077: Bufalin inhibited cell proliferation and expression of insulin-like growth factor 2 and type 1 receptor in human colorectal cancer cells
Authors: Zhang Yong , Feng Dian-Xu , Zhao Ronghua , Chen Chao , Wang Jie , Zuo Qing-Song , Chen Ya-Feng , Wang Xu , Chen Teng 
Published: August 2012

Abstract
Objective: To investigate the inhibitory effect of bufalin on the proliferation of human colorectal cancer cell, HCT116, and its relationship with expression of insulin-like growth factor 2 (IGF-2) and type 1 receptor (IGF1R). Methods: HCT116 cells were cultured with bufalin and cell proliferation was measured by MTT assay. The inhibitory rate of cell proliferation and the half maximal inhibitory concentration (IC50) were calculated. Cell cycle was determined by use of flow cytometry. mRNA and protein expressions of IGF-2 and IGF1R were analyzed by real time polymerase chain reaction (PCR) and Western Blot, respectively. The distribution of IGF-2 and IGF1R in cells was also observed by immunocytochemical staining. Results: The IC50 of bufalin at 24, 36, 48, 60, and 72 hours were 0.79±0.10, 0.37±0.10, 0.25±0.03, 0.17±0.02, and 0.10±0.03 uM, respectively. We selected 0.3 uM and 48 hours as the concentration of bufalin and culture time in following experiments. When cultured with bufalin, the ratio of cells in G2 phase to cells in M phase was increased in a dose dependent manner, indicating a delay from G2 to M caused by bufalin. For IGF-2, the mRNA and protein expressions were increased when cells were cultured with bufalin; For IGF1R, the mRNA increased but protein decreased. Both IGF-2 and IGF1R were seen in cytoplasm. Conclusion: Bufalin can significantly inhibit the proliferation of HCT116 cells, its underlying mechanism may relate with the up-regulation of IGF-2 expression and down-regulation of IGF1R protein expression.
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 1077. doi:1538-7445.AM2012-1077
Abstract 1078: ErbB/Pi3K signaling contributes to EGFR ligand expression in colorectal cancer cells
Authors: Jacobs Bart , Tejpar Sabine 
Published: August 2012

Abstract
Background: Cellular expression of EGFR ligands is tightly regulated and is thought to be maintained by an autocrine signaling component in colorectal cancer cells. More importantly, the expression levels of individual ligands have gained recent interest since their expression of their mRNA was found to be linked to anti-EGFR therapy response. Since the expression of these ligands can be regulated by EGFR signaling elicited by EGF, we decided to investigate the contribution of MAPK as well as the PI3K axis, to EREG expression, in K-Ras wild-type colon cancer cells. Methods Colon cancer cells were used to interrogate EGFR downstream signaling. Several inhibitors targeting the ErbBs and the MAPK and PI3K/Akt pathways were used to dissect the pathways downstream of EGFR maintaining ligand mRNA levels in the lim1215 colon cancer cell line. Additionally, we used ER and AR reporter assays to selectively evaluate involvement of the EGFR pathway in transcriptional regulation of the pathway. Consequently, blockade and activation of EGFR pathway members was assessed by Western Blot. Results We show that Ereg and Areg mRNA levels are specifically maintained by erbb1 signaling. Treatment of lim1215 cells with inhibitors blocking Erbb1 (cetuximab) or ErbB1/Erbb2 (lapatinib) did results in near complete inhibition of Ereg and Areg expression in Kras/pi3K wild-type cells, while blockade of ErbB2 alone (which is activated in these cells) with Trastuzumab did not decrease Ereg nor Areg mRNA levels. Downstream of EGFR, we show that MEK signaling is not required for maintenance of EREG and AREG levels in lim1215 cells. Conversely, blockade of PI3K signaling by Akt inhibitors or PI3K inhibitors abolished EREG mRNA levels in these cells. This was reflected by the ability of overexpressed Akt to induce EREG and AREG reporter activity in 293T cells. In contrast, this activation could be rescued by the addition of Akt and PI3K inhibitors, but not MEK inhibitors in cellular media. Conclusions In this work we show that PI3K signaling is required for the transcription of EGFR ligands in colon cancer cells. In this regard, this provides additional insights to the recent findings that link PI3K/Akt signaling to Receptor Tyrosine Kinase expression and activation in cancer cells. Therefore, a global understanding of the signaling networks that control ligand availability and receptor abundance will be crucial in combining ErbB pathway inhibitors in the treatment of kras wild-type colon cancers.
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 1078. doi:1538-7445.AM2012-1078
Abstract 1189: Discovery of RPS25-MDM2/MDMX-p53 regulatory feedback loop
Authors: Zhang Xu , Wang Wei , Xu Wenrong , Wang Ming-hai , Wang Hui , Zhang Ruiwen 
Published: August 2012

Abstract
There is an increasing interest in elucidation of ribosomal proteins (RPs) in cancer development and progression. Ribosomal proteins have extraribosomal functions and participate in a surveillance network for cell growth, division, and apoptosis. Accumulating evidence suggests that the p53 protein, together with ribosomal proteins, takes part in a surveillance mechanism for genome integrity and protein translation, and is activated by nucleolar stress. We herein identified a regulatory role of RPS25 in p53-mediated cellular response to ribosomal stress. We demonstrated that RPS25 bound to MDM2 by using immunoprecipitation and GST pull-down assays. RPS25 inhibited the E3 ligase activity of MDM2, resulting in the stabilization and activation of p53. Overexpression of RPS25 induced cell cycle arrest and apoptosis through p53. The MDM2-binding and nucleolar location domains of RPS25 were critical for regulating p53 stability and activity. Knockdown of RPS25 by siRNA attenuated the activation of p53 induced by ribosomal stress. Furthermore, we found that MDMX was involved in the regulation of the E3 ligase activity of MDM2 by RPS25, suggesting that RPS25 modulates p53 in an MDM2 and MDMX-dependent manner. Finally, RPS25 was identified to be a transcriptional target of p53. Ribosomal stress-induced p53 activation inhibited RPS25 protein level, while knockdown of p53 restored RPS25 expression. In conclusion, these results demonstrate that RPS25 is a novel regulator of p53 in ribosomal stress and define a unique S25-MDM2/MDMX-p53 regulatory feedback loop in ribosomal stress. (This work was supported by NIH/NCI grants R01 CA112029 and R01 CA121211 and a Susan G Komen Foundation grant BCTR0707731.)
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 1189. doi:1538-7445.AM2012-1189
Abstract 1194: p53 negatively regulates the hepatoma growth factor HDGF
Authors: Tokino Takashi , Idogawa Masashi , Sasaki Yasushi 
Published: August 2012

Abstract
Tumor suppressor genes may exert a significant part of their activity by regulating autocrine and paracrine growth factor pathways. This study reveals how the transcriptional repression function of p53 mediates cancer cell growth and migration. Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression.
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 1194. doi:1538-7445.AM2012-1194
Abstract 1203: Targeting FGFR4 in colorectal cancer cells
Authors: Heinzle Christine , Erdem Zeynep , Sonvilla Gudrun , Stättner Stefan , Karner Josef , Klimpfinger Martin , Grasl-Kraupp Bettina , Holzmann Klaus , Grusch Michael , Berger Walter , Marian Brigitte 
Published: August 2012

Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in the regulation of cell proliferation, differentiation and survival as well as tumor development and therefore constitute prominent targets for cancer therapy. Over-expression of FGFR4 has been described in various cancer types and was also related to tumor aggressiveness. Reports concerning the role of FGFR4 in colorectal cancer (CRC) are still under dispute. In our study we found FGFR4 expression to be significantly up-regulated in human CRC tissue compared to normal mucosa. CRC cell line models over-expressing FGFR4 were created by transfecting SW480, HCT116 and HT29 colon carcinoma cells with a FGFR4 expression vector. This resulted in an increase of cell proliferation and colony formation under standard tissue culture conditions and colony outgrowth in soft agar was stimulated. In xenografted SCID mice tumor growth was significantly increased by FGFR4 over-expression. siRNA mediated knock down of FGFR4 in the high FGFR4 expressing cell lines HCT116 and HT29 resulted in decreased cell proliferation, viability and colony outgrowth in 2-dimensional growth assays. Additionally a dominant negative FGFR4 adenoviral construct inhibited 3-dimensional anchorage independent growth and suppressed tumor growth in vivo almost completely. Ongoing experiments analyze the effects of a soluble FGFR4 variant on 2-dimensional and 3-dimensional growth. FGFR4 up-regulation resulted in activation of survival pathways via FRS2 and PI3K leading to phosphorylation of GSK3β and S6. Signaling effects by blockage of FGFR4 dependent signaling via siRNA and the dominant negative adenoviral construct are currently being investigated. Based on our results we identified the FGFR4 as an important oncogene in the carcinogenesis which is involved in the tumor growth regulation of CRC in vitro and in vivo. Consequently FGFR4 should be regarded as a new therapeutic target in CRC.
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 1203. doi:1538-7445.AM2012-1203