bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3892: Chromosome instability mediated by impaired AuroraB kinase activity on kinetochores in CIN cancer cells
Authors: Haomin Huang , Yen Timothy J. 
Published: February 2011

Abstract
Aneuploidy and chromosome instability (CIN) are hallmarks of solid tumors. Recent studies showed that chromosome missegregation caused by defective kinetochore microtubule attachments during division can give rise to the CIN phenotype. However, the underlying molecular defect that is responsible for the CIN phenotype is poorly understood. On the other hand, increasing evidence suggests that aneuploidy is detrimental to cell growth. Similarly, how CIN cancer cells tolerate a continual state of aneuploidy also remains to be clarified. These are critical questions, given that CIN provides tumor cells a rapid way to adapt to stressful conditions such as chemotherapy.
In this study, we examined a panel of ovarian tumor cell lines and report that they exhibit the CIN phenotype. Timelapse movies showed chromosomes in these cell lines were able to align at the spindle equator but exhibited high rates (numbers) of lagging chromosomes, indicative of aberrant kinetochore: microtubule attachments. This observation was confirmed by the finding that a large fraction (numbers) of kinetochores in these cell lines exhibited a variety of attachment defects relative to Hela cells. As the role of Aurora B kinase at kinetochores is to monitor and repair defective microtubule attachments, we quantitated the levels of Aurora B at kinetochores of these ovarian tumor cell lines. We report that Aurora B levels are reduced relative to Hela cells that do not exhibit attachment defects. Consistent with this finding, FRET studies to monitor the real-time Aurora B kinase activity at the kinetochores of two of the three ovarian cell lines showed that kinase activity was weak. This defect was localized to kinetochores, as the overall activity of Aurora B kinase, as monitored by the western blotting of phospho-Histone H3, was similar to that in Hela cells. These findings provide a molecular explanation for kinetochore attachment defects in these ovarian tumor cell lines and, as a consequence, their chromosome instability.
We also analyzed the response of these cell lines to treatment with various anti-mitotic agents. We found no obvious growth advantage of these ovarian CIN cell lines in response to drugs, relative to Hela cells. Sensitivity to mitotic death may reflect the variation of the genetic background of a given cell line. Also, the mitotic checkpoint appeared to be required for death in mitosis. Although apoptosis clearly played an important role in mitotic cell death in our studies, other death pathways could participate in this event, when apoptosis was blocked.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3892.
Abstract 390: Correlation of the effects of antiangiogenic agents aflibercept (VEGF Trap) and anti-Dll4 antibody on tumor vascular perfusion and tumor growth
Authors: Adler Alexander P. , Eichten Alexandra , Parveen Asma A. , Thurston Gavin 
Published: February 2011

Abstract
Anti-angiogenic treatments are becoming widely used in several major cancer types. Most experimental and clinical development to date has focused on the VEGF pathway, although other signaling pathways, including Dll4-Notch, are also now being explored. However, clinical development for anti-angiogenic therapy has been hindered by a lack of tumor response biomarkers. In this study, we sought to correlate long-term tumor growth responses following blockade of VEGF or Dll4 with rapid effects on tumor vascular perfusion. Using VEGF Trap (aflibercept) and a blocking Dll4 antibody, we compared two tumors that differ widely in their long-term growth responses to each agent: C6 rat glioma tumors (anti-Dll4 resistant, aflibercept sensitive) and HT1080 human fibrosarcoma (anti-Dll4 sensitive, aflibercept resistant), both grown subcutaneously in SCID/CB17 mice. Tumor vascular perfusion was assessed using contrast-enhanced micro-ultrasound at 24 hr after treatment with aflibercept, anti-Dll4 Ab, or the combination, and tumor growth was measured during the course of prolonged twice-weekly treatments. We found that aflibercept treatment rapidly decreased tumor vascular perfusion in C6 tumors (36%) and produced an extended delay in tumor growth (8 days to reach 500mm3). In contrast, anti-Dll4 antibody produced no significant decrease in perfusion of C6 tumors at 24 hr after treatment, and a less dramatic delay in tumor growth (5 days to reach 500mm3). In HT1080 tumors, anti-Dll4 Ab dramatically decreased perfusion (38%), as well as causing a prolonged growth delay (20 days to reach 300mm3), whereas aflibercept caused neither a decrease in perfusion nor growth in these tumors. Unexpectedly, combination treatment with aflibercept and anti-Dll4 was most potent in both tumor types at reducing tumor perfusion and inhibiting tumor growth. Analysis of vascular density by CD31 immunohistochemistry at 24 hr after treatment revealed a decrease in C6 (57% and 31%) and HT1080 (28% and 19%) upon single agent aflibercept and combination treatment, respectively, while anti-Dll4 increased apparent vascular density of C6 tumors (31%) but produced no change in HT1080 tumors. Taken together, these data show that changes in tumor perfusion, but not in vessel density, correlate with long-term tumor responses to aflibercept and anti-Dll4, thus suggesting that decreases in tumor perfusion could be a rapid response biomarker for efficacy of anti-angiogenic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 390.
Abstract 3905: Structure–function relationships between RUNX1-MTG fusion proteins and core components of the Notch transcription complex
Authors: Mariotti Jolene , Nguyen HN , Engel Michael 
Published: February 2011

Abstract
The myeloid translocation genes (MTG) are preferred targets of chromosomal translocations with the Runx1 gene in acute myeloid leukemia (AML) pathogenesis. The resulting fusion proteins, RUNX1-MTG8 and RUNX1-MTG16, influence gene expression programs that control self-renewal and differentiation in hematopoiesis. How they engage the machinery of self-renewal to alter hematopoietic development is poorly understood. To gain additional insights into this question, we investigated structure–function relationships between RUNX1-MTG fusion proteins and core components of the Notch transcription complex, a critical determinant of cell fate specification in diverse tissues. The Notch transcription complex is composed minimally of the transcriptional repressor CSL, the intracellular domain of Notch receptors (N-ICD) and the transcriptional co-activator Mastermind (MAML). We show that RUNX1-MTG fusion proteins transactivate a Notch-responsive element from the Hes1 promoter. Using MTG16 as a model protein, we show that N-ICDs interact with a discrete domain in the MTG N-terminus. We translated these findings to the fusion proteins and found N-ICD binding was retained by RUNX1-MTGs and a RUNX1-MTG16 mutant that lacks the N1-ICD binding site. In parallel experiments, we defined the binding region for MTG proteins and their fusion protein derivatives on the N1-ICD. Informed by these structural relationships, we utilized RUNX1-MTG proteins or mutants that lack N1-ICD binding sites in transcriptional reporter assays. Our findings suggest that RUNX1-MTG fusion proteins alter transcription of the Notch target gene, Hes1 and intimate a structure–function relationship between RUNX1-MTG fusion proteins and Notch signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3905.
Abstract 3906: Twist regulates estrogen receptor expression in breast cancer
Authors: Vesuna Farhad , Lisok Ala , Kimble Brian , Domek John , Kato Yoshinori , Artemov Dmitri , Kowalski Jeanne , Carraway Hetty , van Diest Paul , Raman Venu 
Published: February 2011

Abstract
Background: Estrogen receptor alpha (ER) plays a crucial role in breast cancer development and progression due to its role as an effector/mediator of the mitogenic hormone estrogen. However, the role of transcriptional regulation of ER in tumor progression is not completely characterized. While defining the role of the basic helix loop helix transcription factor Twist (TWIST1) in breast cancer development, we identified ER as a downstream target of Twist in breast cells.
Methods: A knock-up and knock-down approach in Twist negative and positive cell lines was used in order to characterize the regulation of ER by Twist. We analyzed ER expression by immunoblotting, ER transcriptional activity by promoter assays, DNA binding by chromatin immunoprecipitation, and estrogen independent growth in the presence of stripped serum or the estrogen antagonist tamoxifen (TAM). Additionally, ER promoter methylation was measured by methylation specific quantitative PCR (MS-qPCR). Using orthotopic xenografts in SCID mice, tumor growth was determined in presence of TAM and assayed for vascular permeability and volume by functional magnetic resonance imaging. Finally, the relationship between Twist and ER expression in breast tumors was evaluated by quantitative reverse-transcription PCR (qRTPCR).
Results: Twist transcriptionally down-regulated ER expression by direct promoter modulation. Twist over-expression caused estrogen independence and TAM resistance, and induced hypermethylation of the ER promoter. In vivo, Twist expression resulted in estrogen independent growth and resistance to TAM. Twist over-expressing tumor xenografts exhibited high vascular volume and permeability. Moreover, Twist and ER expression were inversely correlated in primary breast cancer patient samples. Conclusion: The regulation of ER by Twist might be an underlying mechanism for ER negativity seen in breast tumors and could have important clinical implications for ER negative breast cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3906.
Abstract 3917: Molecular mechanisms underlying hedgehog-GLI oncogenic function via interaction with the TGF-beta-SMAD4 axis
Authors: Nye Monica D. , Cross Aishah , Almada Lucianna L. , Elsawa Sherine F. , Fernandez-Zapico Martin E. 
Published: February 2011

Abstract
Crosstalk between signaling pathways is crucial to the initiation, progression and maintenance of the transformed phenotype. Therefore, characterization of these signaling interactions is fundamental for the understanding of the complex and varied network of events that leads to the development and spread of tumors. The Hedgehog (HH)-GLI pathway, an important carcinogenic cascade, is required for the growth and survival of tumors of diverse origin. Recent reports, mainly from animal models, suggest that key signaling interactions are required by HH-GLI signaling to modulate cancer-associated cellular functions. However, the molecular mechanisms underlying this phenomenon in cancer and non-cancer cells remain elusive. Our preliminary data show a crosstalk between the HH-GLI axis and TGF-beta pathway, a well-characterized tumor suppressor/oncogenic signaling pathway. Luciferase reporter and expression assays in combination with genetic and pharmacological manipulations of the TGFbeta pathway show that this cascade is able to activate GLI transcriptional activity, even in the absence of an active HH signaling. The TGFbeta pathway is required to maintain active GLI transcriptional complexes at GLI target genes. Further analysis of this molecular interaction suggests that TGFbeta pathway-mediated activation of GLI transcription factors requires an intact SMAD4, thus suggesting a potential mechanism mediating this functional interaction. The knowledge derived from this study provides both mechanistic insight into the contribution of this HH-GLI/TGF-beta pathway interaction to carcinogenesis and could serve as a foundation for development of new therapeutic approaches for tumors with active HH-GLI and TGF cascades.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3917.
Abstract 3919: Potential roles of oncogenic ΔNP63α during bone and bone cancer formation
Authors: Abbassi Sam , Ding Ming , Li Feifei , Lu Yaojuan , Wu Guojun , Zheng Qiping 
Published: February 2011

Abstract
P63 belongs to the P53 tumor suppressor gene family. Due to its alternative promoter usage and splicing, p63 consists of two major subtypes (TAp63 and ΔNp63) and six different isoforms (TAp63α, β, or γ and ΔNp63α, β, or γ). These isoforms have been shown to play distinct biological functions in cancer and development. P63, especially the ΔNp63α variant, has been suggested to play an oncogenic role in cancer progression, including bone-related tumors such as giant cell tumor of bone and osteosarcoma. Interestingly, P63 has previously been shown to be an essential player for limb development. This raises the possibility that there might be a specific mechanism linking P63 regulation of bone and bone cancer formation.
The type X collagen gene (Col10a1) is a specific marker of hypertrophic chondrocytes during endochondral bone formation. As a matrix protein, type X collagen also functions as a regulatory molecule that affects chondrocyte mineralization, apoptosis, and angiogenesis. Therefore, transcriptional regulators critical for Col10a1 expression are also expected to affect the apoptotic pathway that occurs during bone cancer formation. By real-time RT-PCR and proteomic approaches using a MCT cell model, we demonstrate here that P63 contributes to regulation of Col10a1 expression in vitro. We also have data which supports that Runx2 regulates cell-specific Col10a1 expression via the Runx2 binding sites found within the Col10a1 cis-enhancer. This is intriguing since p63 was previously shown to interact with Runx2 by yeast two-hybrid approach. Moreover, we have generated a mouse model in which Runx2 was driven by the cell-specific Col10a1 control element. Our preliminary results showed that these Col10a1-Runx2 transgenic mice have enhanced Runx2 and Col10a1 expression, a longer hypertrophic zone, altered chondrocyte maturation, apoptosis, and disturbed ossification. These results suggest the decreased apoptotic activity mediated by Runx2, whereas elevated Runx2 expression has been associated with osteosarcoma development and chondrosarcoma progression. To address the potential in vivo relevance of P63 on bone and cancer formation, we have established Col10a1-ΔNp63α transgenic mouse lines using the same Col10a1 control element. Characterization of these transgenic mice will allow us to study if this oncogenic P63 isoform regulates Col10a1 expression in vivo and if this regulation is within the network regulating both bone and bone cancer formation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3919.
Abstract 3961: Chemotherapy treatment induces an Interleukin-6 deficit in the bone marrow microenvironment
Authors: Rellick Stephanie , Piktel Debra , Walton Cheryl , O'Leary Heather , Othumpangat Sreekumar , Hall Brett , Craig Michael , Gibson Laura F. 
Published: February 2011

Abstract
Bone marrow stromal cells (BMSC) are a critical component of the microenvironment that supports hematopoiesis, and hematopoietic recovery following bone marrow transplantation. Aggressive chemotherapy not only affects tumor cells, but also influences structural and functional components of the microenvironment, including BMSC and osteoblasts. Successful stem cell or bone marrow transplantation following immuno-suppressive or myeloablative chemotherapy is dependent on the ability of BMSC, and other cellular components of the microenvironment, to maintain their functionality. This includes secretion of soluble factors and expression of cellular adhesion molecules that are critical for the survival, proliferation, and differentiation of immature progenitor cells. In the current study, we have investigated the effects of chemotherapy treatment on BMSC and human osteoblast (HOB) expression of Interleukin-6 (IL-6). IL-6 is a pleiotrophic cytokine which has diverse effects on hematopoietic cell development. The treatment of BMSC or HOB with Melphalan or VP-16, which are clinically relevant drugs used in pre-transplant regimens, led to decreased IL-6 protein expression. This decrease in IL-6 protein is unique to Melphalan, as treatment with other chemotherapeutic agents does not result in a similar decrease in IL-6 protein. We have also observed a decrease in gp130, the transmembrane protein necessary for IL-6 signaling, in response to Melphalan treatment, but not VP-16 treatment. Additionally, pre-treatment of BMSC and HOB with Z-VAD-FMK or Leupeptin, a broad range caspase inhibitor and lysosomal inhibitor respectively, prior to chemotherapy treatment was not able to blunt the decrease in IL-6 protein detected in cell supernatants. These data suggest chemotherapy is not enhancing the degradation of IL-6 protein through caspase or lysosomal mediated mechanisms, but rather blunting the overall expression of IL-6. Melphalan treatment is also able to decrease IL-6 mRNA and further investigation is necessary to determine the mechanism by which chemotherapy affects transcription of IL-6. Collectively, these observations suggest that chemotherapy treatment induced alteration of bone marrow microenvironment function, which results in decreased or defective hematopoietic support of human embryonic stem cells and early progenitor cells may result, in part, from an IL-6 deficit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3961.
Abstract 3974: TIAF1 blocks p53 suppression of SMAD promoter activation
Authors: Chang Nan-Shan , Hsu Li-Jin , Lee Ming-Hui , Lin Sing-Ru 
Published: February 2011

Abstract
p53 participates in the TGF-β signaling. How p53 regulates SMAD gene transcription is largely unknown. TIAF1 is a TGF-β1-induced factor and a downstream effector of the TGF-β signaling. TIAF1 is known to control nuclear localization of Ser15-phosphorylated p53. Ectopic TIAF1 induces growth inhibition and apoptosis of monocytic U937 and many non-fibroblasts, via upregulation of p53, p21, and Smad2/4, but downregulation of ERK phosphorylation. Wild type p53 suppresses the transcriptional activation of SMAD gene, whereas isoform p53γ induces the gene activation. TGF-β1 increases the physical association of TIAF1 with Smad4, and when overexpressed, TIAF1 inhibits Smad4-dependent promoter activation. In combination, TIAF1 and p53 support the promoter activation regulated by endogenous or ectopic Smad4, indicating that TIAF1 blocks p53 suppression of the SMAD promoter activation, and vice versa. Without Ser46 phosphorylation in p53 (p53ΔS46), p53ΔS46 alone, or in the co-presence of TIAF1, abolishes the Smad4-regulated promoter activation. These observations suggest a critical role of Ser46 in p53 in controlling SMAD transcriptional activation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3974.
Abstract 3980: Quantitative detection of discriminatory proteins in tissue and serum of ovarian cancer patients by LC-MSE
Authors: Wegdam Wouter , Kramer Gertjan , Langridge James , Moerland Perry D. , de Jong Shreyas M. , Vissers Johannes P. , Kenter Gemma G. , Buist Marrije R. , Aerts Johannes M.F.G. 
Published: February 2011

Abstract
Purpose
To search for potential protein markers or activated pathways which play a role in ovarian cancer.
Experimental procedures
Serum of six patients with a serous adenocarcinoma of the ovary (stage IIIB or higher) was collected before treatment. Matched control patients with a serous cystadenoma of the ovary were chosen as a control group. In addition, homogeneous regions of cells that exhibited uniform histology were isolated from cancer tissue in three of these patients by laser capture microdissection (LCM), normal ovarian epithelial cell samples were taken from their matched controls. Subsequently we employed label-free liquid chromatography tandem mass spectrometry (LC-MSE) to identify proteins and determine their absolute concentrations in serum specimens and tissue lysates. Moderated t-tests were used to identify differentially expressed proteins between patient- and control-group, p-values were adjusted for multiple-testing using Benjamini-Hochberg false discovery rates. Proteins were considered to be differentially expressed if the adjusted p-values were &lt;0.05.
Summary of the data
In the serum specimens, 13 differentially expressed proteins were identified by LC-MSE profiling. Proteins with different concentrations in patients versus control sera include abundant serum proteins such as apolipoprotein AI and transferrin, that both exhibited a lower concentration in serum of cancer patients. Differential expression was also observed for apolipoproteins (APOA IV, APOA II and APOC III) and other proteins that have not been associated with ovarian cancer previously such as C9 and Afamin.
In the tissue lysates, 17 differentially expressed proteins were identified. Amounts of collagen found were decreased in cancer tissue. Furthermore, proteins associated with the respiratory chain and cell migration were found in increased amounts in the cancer tissue lysates.
Interestingly, no overlap was found between the discriminatory proteins in serum specimens and corresponding tissue lysates, illustrating the challenge to identify a single biomarker in the circulation reflecting ovary cancer.
Conclusions
Our study revealed several protein changes in serum and the ovary of patients suffering from serous adenocarcinoma of the ovary (stage IIIB or higher). Further investigation of these proteins is warranted to establish whether they could provide new insights into the etiology of the disease and act as potential new disease markers.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3980.