bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4766: Multivalent VRP-based anti-tumor immunotherapy is an effective therapeutic strategy in a rat model of breast cancer
Authors: Laust Amanda K. , Mkrtichyan Mikayel , Davtyan Hayk , Khlgatyan Jivan , Ghochikyan Anahit , Liu Han , Agadjanyan Michael G. , Nelson Edward L. 
Published: February 2011

Abstract
It is widely accepted that the genetic instability of a tumor results in both intra- and inter-tumoral genetic heterogeneity, which leads to heterogeneous tumor-associated antigen (TAA) expression and contributes to the outgrowth of antigen-loss variants in response to immunologic selective pressure. Using a rat neu encoding, alphavirus based virus-like replicon particle (VRP) with restricted in vivo tropism for dendritic cells in a fully tolerant Fisher 344 rat mammary tumor (13762 MAT B III) model, we previously demonstrated the ability to cure a modest proportion, 20-40%, of rats with pre-existing mammary tumors and observed the outgrowth of antigen loss variant tumors in a proportion of animals that ultimately succumbed to their tumor. Thus, we hypothesized that strategies targeting multiple tumor antigens would lead to improved treatment efficacy. Expression of the cancer testes antigen, Brother of Regulator of Imprinted Sites (BORIS) was confirmed in the 13762 MAT B III tumor. Rats with pre-existing tumors were treated with VRP encoding either the TAA rat neu or the BORIS target antigen, alone or in combination. We found that targeting either rat neu or BORIS alone was effective in treating a proportion of animals. Interestingly, administration of both VRP agents at a single anatomic site drastically decreased the treatment efficacy, by approximately 50%, while separating their administration into two separate anatomic sites enhanced the treatment efficacy over that provided by each agent alone, to &gt;56% cure rate. Herein, we will present data addressing potential mechanisms for these treatment observations. To our knowledge, this is the first report of multivalent anti-tumor immunotherapy utilizing solely the VRP vector system. These data represent an exceptionally promising platform upon which to build more efficacious immunotherapeutic strategies including those targeting multiple defined TAAs.
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 4766.
Abstract 4801: Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer
Authors: Liang Gangning , Wolff Erika M. , Han Han F. , Byun Hyany-Min , Sharma Shikhar , Nichols Peter , Siegmund Kimberly D. , Jones Peter A. 
Published: February 2011

Abstract
Background: It was recently shown that a large portion of the human transcriptome can originate from within repetitive elements, leading to ectopic expression of protein-coding genes. However the mechanism of transcriptional activation of repetitive elements has not been definitively elucidated.
Principal findings: For the first time, we directly demonstrate that hypomethylation of retrotransposons causes altered gene expression in humans. We also reveal that active LINE-1s switch from a tetranucleosome to dinucleosome structure, acquiring H2A.Z and nucleosome free regions upstream of TSSs, previously shown only at active single copy genes. Hypomethylation of a specific LINE-1 promoter was also found to induce an alternate transcript of the MET oncogene in bladder tumors and across the entire urothelium of tumor-bearing bladders.
Conclusions: These data show that, in addition to contributing to chromosomal instability, hypomethylation of LINE-1s can alter the functional transcriptome and plays a role not only in human disease but also in disease predisposition.
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 4801.
Abstract 4806: Breast carcinoma DNA methylation profiles are associated with tumor size, alcohol intake, and folate intake
Authors: Christensen Brock C. , Kelsey Karl T. , Houseman E. Andres , Marsit Carmen J. , Zheng Shichun , Wrensch Margaret R. , Wiemels Joseph L. , Nelson Heather H. , Karagas Margaret R. , Kushi Lawrence H. , Kwan Marilyn L. , Wiencke John K. 
Published: February 2011

Abstract
The cornerstones of breast cancer prognosis and management are tumor size and axillary lymph node involvement. We investigated both individual genes and overall patterns of methylation in relation to these and other tumor characteristic along with environmental exposure variables. The Illumina GoldenGate methylation bead-array platform was used to measure 1413 autosomal CpG loci associated with 773 cancer-related genes in 162 FFPE primary breast tumors (AJCC stage I-IV) from the Pathways Study. From CpG locus-by-locus tests, the strongest methylation associations (based on the number of CpG loci with Q-values &lt; 0.05) were for tumor grade (209 loci), tumor size (74 loci), estrogen receptor status (183 loci), progesterone receptor status (69 loci), and triple negative status (130 loci). Unsupervised clustering, using a recursively partitioned mixture model (RPMM), of all autosomal CpG loci across all tumors resulted in eight distinct methylation profile classes, and class membership was significantly associated with patient race (P &lt; 0.02) and tumor size (P &lt; 0.001). Using multinomial logistic regression to adjust for potential confounders, patient age, alcohol intake, total dietary folic acid intake, and tumor size were all significantly associated with tumor methylation profile (all P &lt; 0.0001). Furthermore, there were opposite trends of methylation for increasing alcohol and folate intake, which were associated with decreased and increased methylation, respectively. Lymph node status, tumor grade, estrogen receptor status and tumor histology were not associated with methylation class in the multinomial model. In an RPMM of tumors from postmenopausal patients only, methylation class membership was significantly associated with estrogen receptor status (P &lt; 0.03). Selected CpG loci were validated with Sequenom EpiTYPER methylation analysis and methylation of several candidate genes were associated with silencing of gene expression. Taken together, these data demonstrate strong associations between both specific gene methylation and overall DNA methylation profiles and tumor characteristic and patient exposure history.
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 4806.
Abstract 4808: SIAH2-dependent proteolysis in cell migration, tumor growth, and cancer metastasis
Authors: Liao Yang , Schmidt Rebecca R. , Walton Zandra , Tang Amy H. 
Published: February 2011

Abstract
The dismal prognosis of patients diagnosed with invasive and metastatic cancer points to our limited arsenal of effective anticancer therapies. The central importance of EGFR/HER2/RAS pathway activation has been well established in neoplastic transformation and tumorigenesis. An important goal in cancer biology is to identify novel and effective means to inhibit activated EGFR/HER2/K-RAS signals and reverse malignant transformation, tumor growth and cancer metastasis. SIAHs are the human homologs of Drosophila Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase that is an essential downstream signaling module and critical “gatekeeper” required for RAS signal transduction in human cancer cells. By targeting the most downstream signaling module identified in the RAS pathway - the SIAH2 proteolytic machinery, we are able to block tumorigenesis and metastasis in multiple of the most aggressive forms of human cancer cells known in athymic nude mice. Although we are fully cognizant of the systemic limitation in the xenograft models and incomplete mimicry of the full-spectrum metastatic processes observed in athymic nude mice, we are encouraged by the impressive anti-SIAH2-based tumor suppression in these preclinical studies. In this study, we aim to identify the molecular mechanism(s) of SIAH2 action in human cancer cells. To delineate SIAH2 function in cancer, through a proteomic approach, we identified three endogenous LIM domain proteins, TRIP6/FHL2/LPXN, as the bona fide SIAH2-interacting proteins isolated from the most aggressive human cancer cell lines (A549, MiaPaCa and MDA-MB-435 cells) in parallel. We provide extensive biochemical evidence to show that TRIP6/FHL2/LPXN are bona fide SIAH2 substrates. These new SIAH2 substrates can successfully rescue cell motility and viability defects observed in SIAH2-deficient cancer cells, suggesting that these focal adhesion proteins may represent one of many diverse signaling modules that function downstream of SIAH2 in mediating aspects of RAS-dependent signaling in normal development and cancer. Our results suggest In response to ERBB/RAS activation, SIAH2 E3 ligase modulates cell junction, adhesion and migration by targeting focal adhesion proteins for ubiquitin-mediated proteolysis to promote cell migration, tumorigenesis and metastasis in human cancer cells. The identification of SIAH2-mediated focal adhesion and cell junction modulation may have important implications in cancer biology to explain the well-documented modulations in focal adhesion, cell junction and motility in response to ERBB/RAS activation in human cancer cells.
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 4808.
Abstract 482: The HER-2 erbB receptor is vital for growth of breast cancer cells in bone
Authors: Dawsey Scott J. , Ignatoski Kathleen M. Woods , Day Kathleen C. 
Published: February 2011

Abstract
HER-2 is a receptor tyrosine kinase that has been shown to be over expressed in 30% of human primary breast cancers (BrCa). Our animal model data and human bone met data, which we present here, indicates that HER-2 up-regulation is required for breast cancer cells to grow in and remodel bone. However, most bone metastases from BrCa will arise from a primary diagnosis of ER positive/HER-2 negative disease. We found that MCF-7 cells, an ER positive/HER-2 negative breast cancer model, formed tumors in bone that had up-regulated HER-2 protein expression. In order to directly test whether or not HER-2 expression has an affect on bone metastasis, we engineered a knock down of the HER-2 receptor in MCF-7 cells by utilizing a lentivirus plasmid containing the shRNA to the HER-2 receptor. Both the shRNA HER-2 knock-down and the vector-only control expressed the Green Fluorescence Protein (GFP) and puromycin resistance for plasmid selection. Our engineered MCF-7 control cells (shVector alone) or the HER-2 knock-down (shHER-2) were injected into the tibia of SCID mice. We found that both the vector-only and HER-2 knock-down cells grew tumors in mouse tibia. Anti-HER-2 immunohistochemical (IHC) analysis showed that the HER-2 protein was re-expressed in the knock down cells in tumors formed in tibiae. Additionally, we found that in eight patients with breast cancer bone metastasis, 100% of these cases contained a significant expression of HER-2 positive cells by IHC. As confirmation of our mouse studies, we found that all of the human bone biopsies obtained from ER positive/HER-2 negative disease were up-regulated for HER-2 in the bone microenvironment. Concomitant with our human data, MCF-7 cells required exogenous estrogen to form tumors in mammary fat pads and did not require exogenous estrogen to form tumors in bone. Therefore, we believe that BrCa cells can change, up-regulate protein expression of HER-2, and become estrogen independent in the bone microenvironment. It may be that these women could benefit from intervention with agents against HER-2.
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 482.
Abstract 4825: Serum selenium concentration and risk of colorectal cancer in postmenopausal women: The Women's Health Initiative Observational Study
Authors: Takata Yumie , King Irena B. , Song Xiaoling , Diamond Alan M. , Foster Charles B. , Hutter Carolyn M. , Hsu Li , Duggan David J. , Langer Robert D. , Petrovitch Helen , Shikany James M. , Vaughan Thomas L. , Kristal Alan R. , Lampe Johanna W. , Prentice Ross L. , Peters Ulrike 
Published: February 2011

Abstract
In vitro and animal experimental studies have reported beneficial effects of selenium on colorectal cancer (CRC), yet results from epidemiological studies are inconsistent. Few of these studies have examined CRC risk among women, and none have been sufficiently large to examine risk in subgroups. This study investigated whether baseline serum selenium concentration was associated with subsequent CRC risk among postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. We included 804 CRC cases diagnosed between October 1993 and September 2005 and 804 controls matched to cases on age, enrollment date, clinical center, race/ethnicity, hysterectomy status, and prevalent condition at baseline. Baseline serum selenium concentration was measured by atomic absorption spectrometry. Multivariate logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) associated with increasing serum selenium concentrations. The corresponding median selenium concentrations in the 1st to 5th quintiles were 110.5, 123.2, 133.5, 144.8, and 162.2 µg/l (range: 81.03 - 398.70 µg/l). The selenium concentration was weakly and positively associated with the risk of CRC (ptrend = 0.08); the adjusted ORs (95% CIs) for the risk of CRC comparing the 2nd, 3rd, 4th, and 5th quintile of serum selenium concentrations with the 1st quintile were 1.14 (0.83-1.58), 1.16 (0.84-1.60), 1.36 (0.99-1.87) and 1.27 (0.92-1.76). The trend was somewhat stronger for past and current smokers [OR (95% CI) for the 5th vs. 1st quintile = 1.38 (0.89-2.13), ptrend = 0.13] than never smokers [OR (95% CI) for the 5th vs. 1st quintile = 1.16 (0.72-1.87), ptrend = 0.48]. However, the difference was not statistically significant (pinteraction = 0.53). Findings from this large study with relatively high serum selenium concentrations suggest no beneficial effect of selenium on colorectal cancer among women, which is consistent with results of previous smaller observational studies.
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 4825.
Abstract 4847: Arginine deprivation by PEG-ADI induces autophagic cell death and enhances the tumor suppression effect of gemcitabine in pancreatic cancer
Authors: Daylami Rouzbeh , Muilenburg Diego , Bowles Tawnya L. , Martinez Steve R. , Bold Richard J. 
Published: February 2011

Abstract
Metabolic stress has been recently recognized to induce autophagic cell death; we have recently shown that nearly 80% of pancreatic adenocarcinoma tumor specimens are auxotrophic for the semi-essential amino acid arginine due to transcriptional suppression of argininosuccinate synthase (ASS). We hypothesized that selective arginine deprivation would induce autophagy and furthermore, by targeting alternative death pathways would increase the cytotoxic response to the chemotherapy gemcitabine.
Methods: The human pancreatic cell line MIA-PaCa-2 was shown to be deficient in ASS by western blot. Arginine deprivation was achieved by treatment of cells and xenografts with PEG-ADI, which shuttles arginine to citrulline. Cells were treated with either PEG-ADI, gemcitabine or both. Cell death was measured by MTT and FACS. Western blot was used to measure autophagy by LC3 processing and apoptosis by caspase-3 cleavage. RRM2 expression was measured by western blot in cells treated with PEG-ADI. ASS expression was measured by western blot in cells treated with gemcitabine. To test the in vivo effect arginine deprivation a mice xenograft model was created by subcutaneously injecting Mia-PaCa2 cells into the flanks of 28 mice (two tumors per mice). Tumors were allowed to mature at which time the mice were assigned to one of four treatment groups: PBS control (once weekly), ADI-PEG20 (5 IU once weekly), Gemcitabine (125mg/kg twice weekly), or Gemcitabine and ADI-PEG20. All treatments were administered via intraperitoneal injection and tumors were measured twice a week.
Results: 1. MIA-PaCa-2 lacks ASS and is auxotrophic for arginine. 2. PEG-ADI induces autophagy and cell death 3. Gemcitabine has little in vitro cytotoxicity 4. The combination of gemcitabine and PEG-ADI is at least additive in vitro and in vivo. 5. PEG-ADI does not regulate RRM2 expression and gemcitabine does not regulate ASS expression.
Conclusions: Therapy targeting autophagy may provide increased efficacy for traditional genotoxic chemotherapies in pancreatic cancer. PEG-ADI in combination with gemcitabine is a novel combination to be pursued in clinical trials
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 4847.
Abstract 4849: Role of autophagy in breast cancer metastasis and treatment
Authors: Maycotte Paola , Thorburn Jackie , Thorburn Andrew 
Published: February 2011

Abstract
Autophagy has shown to be important for tissue homeostasis and many human diseases as well as cancer. However, in cancer its role is controversial because autophagy may both promote and inhibit tumor development and progression. In cancer treatment, autophagy may control the likelihood with which tumor cells die but for different treatments and different tumors these effects may be opposite.
Breast cancer is the most common type of cancer in women in the US; and, although it is not yet clear how should we manipulate autophagy in people with cancer, autophagy is already being manipulated in breast cancer patients in clinical trials. Moreover, because most anti-cancer treatments induce autophagy, we may also be inadvertently manipulating autophagy in the majority of breast cancer patients.
To evaluate if autophagy is important in breast cancer progression and treatment, we used murine 4T1 cells, a model of metastatic breast cancer. Using matched tumor cells with different metastatic potential we found that basal autophagy was increased with increasing metastasis implying that autophagy is required to allow metastatic progression. To test if treatments that are used for metastatic breast cancer were affected by autophagy, we examined LC3 processing after 4T1 cell treatment with common breast cancer treatments including etoposide, cisplatin, doxorubicin and cyclophosphamide. In all cases, these drugs increased autophagy; however, although autophagy inhibition with chloroquine treatment increased cell death in clonogenic assays, Atg12 knockdown in 4T1 cells had no effect on either long or short term viability assays after treatment with the four chemotherapeutic drugs. Thus, we hypothesize that inhibition of specific steps in the autophagic pathway might have different effects on cell viability after treatment. Further testing of this hypothesis will be discussed.
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 4849.
Abstract 4850: Tumor mitochondria contribute to autophagic properties of the cancer cells
Authors: Tu Yi-Fang , Ma Yewei , Wong Lee-Jun C. 
Published: February 2011

Abstract
Autophagy is a cellular housekeeping process that removes damaged or unwanted cellular components and recycles them to build new constituents. It is essential for tumor growth under adverse environment. Mitochondria play an important role in the formation of autophagosome and its subsequent docking and fusion with lysosome. In order to study the contribution of mitochondria to the regulation of homeostatic autophagy in cancer cells, we used a transmitochondrial cytoplasmic hybrid (cybrid) system to investigate the role of tumor-derived mitochondria in a defined nuclear background. Since LC3-II is the autophagosomal membrane-bound form of microtubule-associated protein 1 light chain 3 (LC3-I), increased LC3-II or increased LC3-II/LC3-I ratio is an indication of activation of autophagy. Cybrids containing mitochondria derived from a highly metastatic breast cancer cell line MDA-MB-231 (c231) exhibited lower LC-II levels but higher ratio of LC3-II/LC-I than other cybrids containing mitochondria derived from low or moderate metastatic breast cancer cell lines MDA-MB-436 and MDA-MB-468, as well as mammary epithelial cell MCF-10A (c10A). Increase of LC3 puncta on immunofluorescence stain and decrease of sequestosome 1 (p62/SQSTM1), a marker of autophagic flux, in c231 cells, compared to other cybrids, further indicated that mitochondria derived from high metastatic breast cancer cell line MDA-MB-231 could increase autophagy and accelerate autophagic flux. The accelerated autophagic flux in c231 cells can be blocked by the autophagy inhibitor bafilomycin-A1. In addition, the mitochondria in c231 cells were noted to promote mitochondrial permeability transition (MPT) and were surrounded by LC3 puncta. These results suggested that tumor mitochondria from highly metastatic breast cancer cell line, MDA-MB-231, can promote homeostatic autophagy of cancer.
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 4850.