bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1286: Elucidating the role of E2F2 in mediating human breast cancer metastasis
Authors: Yuwanita Inez , Barnes Danielle , Andrechek Eran 
Published: August 2012

Abstract
In human breast cancer it is not the primary tumor that is the cause of mortality but tumor metastasis to distant sites. Therefore, it is important to elucidate the biological mechanisms that underlie the metastatic processes. To address this, we utilized bioinformatic methods in combination with biochemical assays and genetic studies. Specifically, we crossed MMTV-Myc transgenic mice with various activator E2Fs mutants. We found that the tumor incidence decreased in MMTV-Myc mice interbred with E2F2 and E2F3 mutant backgrounds. Surprisingly, we also found that the loss of E2F2 sharply increased the percentage of lung metastasis in MMTV-Myc mice. Here, we test whether these observations in mice translate to human breast cancer and identify the genes under the control of E2F2 transcription factor that are responsible for mediating breast cancer metastasis. To achieve these aims, we examined the probability of activation of the E2F2 transcription factors in human breast cancer. We calculated the probability of E2F2 activation and used this data to stratify the human breast cancer samples and their associated metastatic clinical data. Examining this data we found that a low probability of E2F2 pathway activation led to decreased time to distant metastasis. To account for this discrepancy, we performed hierarchical clustering of human and mouse gene expression datasets. We found two clusters of human breast tumors in which E2F2 played distinctly different roles in mediating metastasis. One particular cluster clustered with our mouse gene expression data and exhibited the same role for E2F2 where it increased time to distant metastasis. In addition, we examined the ontology of the genes in this cluster and found that the majority of these genes had putative E2F binding sites. To further identify genes that are involved in metastasis, we stratified human breast cancer metastasis clinical annotation using gene expression values from these genes. We found that there were seven genes that are uniquely differentially regulated in this cluster. Interestingly, we observed that this group of seven genes included genes that were implicated in the metastatic process such as MMP16. Taken together, our results showed that there is an important role for E2F2 in mediating breast cancer metastasis and using our bioinformatic methods, we have begun to elucidate this role of E2F2 in mediating breast cancer metastasis. Our future directions include further validation of these target genes in vitro and in vivo to establish the mechanism by which E2F2 mediates breast cancer metastasis.
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 1286. doi:1538-7445.AM2012-1286
Abstract 1296: Identification of human nuclear factor 1 (NF-1) as a potential transcription factor which regulates the gene expression of Sulfotransferase isoform 1A1 (SULT1A1) in human breast cancer
Authors: Yao-Borengasser Aiwei , Yu Xinfeng , Dhakal Ishwori B. , Edavana Vineetha K. , Williams Suzanne , Kadlubar Susan A. 
Published: August 2012

Abstract
Sulfotransferase isoform 1A1 (SULT1A1) plays a central role in drug metabolism. SULT1A1 expression is tissue specific, with little to no expression in normal breast epithelia but plentiful protein expression in most breast tumors. Revelation of the regulators of SULT1A1 expression in breast tissues is important in predicting breast tissue response to therapeutic agents that are substrates of SULT1A1, particularly tamoxifen which can be used for both breast cancer treatment and chemoprevention. In order to identify the appropriate transcription factors that regulate the gene expression of SULT1A1, we performed transcription factor (TF) Activation Profiling Plate Array assay (Signosis, Sunnyvale, CA) in normal breast MCF10A cells and breast cancer ZR-75 cells. TF activation profile differences in MCF10A cells and ZR-75 cells were quantitatively analyzed and compared. Out of 48 TFs DNA-binding activities allowed per plate, 18 TFs’ activities were at least 1.5 fold higher in ZR75 cells compared to that of in MCF10A cells. Matching of the 18 TFs to the possible TF binding consensus sequences in SULT1A1, which were predicted by software Alibaba 2.0, was performed and we found that nuclear factor 1 (NF-1) and GATA transcription factor 1 (GATA-1) were putative transcription factors involved in the regulation of SULT1A1 expression. To further study the relationship between NF-1 and GATA-1 and SULT1A1, we measured mRNA levels of NF-1, GATA-1, and SULT1A1 using total RNA isolated from 97 human liver samples. The liver samples were obtained from 43 female and 54 male health subjects (age range 26-102 year, mean 59.0 years). The real-time RT-PCR results showed that only NF-1, not GATA-1, mRNA level showed significant correlation with SULT1A1 mRNA level (r=0.64, p&lt;0.0001). Therefore, we have identified that NF-1 as a new strong candidate for SULT1A1 gene expression regulation. The finding has laid foundation for the study on the effect of NF-1 on SULT1A1 gene expression, which could provide a mechanistic explanation for the differential expression of SULT1A1 between normal breast tissue and breast tumors.
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 1296. doi:1538-7445.AM2012-1296
Abstract 1299: PHD3 has a key role in survival and proliferation of renal carcinoma cells
Authors: Park Byeong Woo , Kim Kyung-Sup , Park Seho , Park Hyung Seok , Kim Lee-Su 
Published: August 2012

Abstract
Prolyl hydroxylase domain-containing protein3 (PHD3) is one of enzymes catalyzing proline-hydroxylation of hypoxia inducible factor(HIF)α- subunits, which is key regulatory event of HIF activity. In renal cell carcinoma (RCC) tissues, PHD3 is commonly expressed at markedly higher level than surrounding normal tissue. PHD3 is one of the target genes, of which the expressions are induced by HIFs. Because high level of HIF activities is known to play a crucial role in tumorigenesis of RCC, the control of PHD3 by HIFs is simply expected to be negative feedback loop. However, PHD3 shows strong tumorigenic effects in RCC by itself. The forced expression of PHD3 in Caki-1, where PDH3 is expressed at low level, stimulated the proliferation and led to tumor formation in xenografted nude mice. The knocking-down of PHD3 in A498 and 768-O RCC cell lines, where PHD3 is highly expressed, severely inhibited the cell-cycle progression and the proliferation. A498 tumors formed in xenografted nude mice were effectively shrinked by injection of lentivirus expression shRNA for PHD3. When the conditional expression system of shRNA for PHD3 was introduced to A498 cells, the xenografted tumors were completed disappeared by administration of doxycycline. The expression of p57KIP2 is characteristically reduced in RCC tissues.
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 1299. doi:1538-7445.AM2012-1299
Abstract 13: Expression of mutant c-KIT isoforms in fibroblasts causes tumorigenic transformation
Authors: Thaiwong Tuddow , Kiupel Matti , Yuzbasiyan-Gurkan Vilma 
Published: August 2012

Abstract
The type III membrane tyrosine kinase receptor c-KIT is a proto-oncogene and has been shown to harbor activating mutations in a variety of cancers in humans and dogs. Specifically, deletion in codon 556-558, changing VQWKVV to VQFV (Del2) and deletion in codon 556-557, changing VQWKVV to VQVV (Del9) have been observed in both human and canine human gastrointestinal stromal tumors (GISTs). These and similar deletions are also found in some canine mast cell tumors (MCTs). In addition, internal tandem repeat duplications in exon 11 are also observed in canine MCTs. However, the significance of these mutations in driving the tumorigenic process has not been previously assessed. To directly test the hypothesis that mutant c-KIT isoforms observed in spontaneous tumors in humans and dogs are capable of driving the tumorigenic process, each isoform was ectopically expressed in canine primary fibroblasts which normally do not express c-KIT. Transfection of cells with constructs each expressing either the two exon 11 deletion mutants (Del2 and Del9) and one exon 11 duplication mutant, but not normal c-KIT, resulted in neoplastic transformation in vitro. Each transformed cell line was evaluated for the tumorigenic phenotype via the ability to invade matrigel, grow on soft agar and grow in low serum. All transformed cells displayed an invasive tumorigenic phenotype in contrast to normal fibroblasts. In vivo tumorigencity of each transformed cell line was evaluated using subcutaneous injection of one hundred thousand or one million cells of each cell line at three sites each in NSG (NOD scid gamma) immunodeficient mice. All transformed cell lines resulted in tumors at the injection site regardless of the dose. Histologically, all appeared to be sarcomas, with some showing ostoid deposition, thereby warranting the diagnosis of osteosarcoma. With Del2 transformed cells, five of the six tumors were osteosarcomas with two showing metastatic lesions upon necropsy. With Del9 transformed cells three out of six tumors were osteosarcomas and no metastasis was noted. With the duplication mutation three out of the six tumors were osteosarcoma. These findings provide strong support that these mutant c-KIT isoforms are sufficient to derive the tumorigenic process.
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 13. doi:1538-7445.AM2012-13
Abstract 1447: Investigating susceptibility to sporadic osteosarcoma by genome-wide copy number analysis
Authors: Porat Rinnat M. , Pasic Ivan , Shlien Adan , Gokgoz Nalan , Andrulis Irene , Wunder Jay S. , Malkin David 
Published: August 2012

Abstract
Constitutional copy-number variants (CNVs) frequently overlap genomic regions that contain genes associated with cancer. In addition, copy number alterations (CNAs) in tumors often coincide with sites of CNVs and may arise through progression of CNVs. Osteosarcoma (OS), the most common human bone malignancy, can arise in familial or sporadic forms. While germline mutations of tumor suppressor genes have been implicated in a minority of OS cases, little is known about genetic changes that contribute to the etiology of sporadic OS. Using high-resolution SNP/CNV arrays, we observed a higher global germline CNV frequency in patients with sporadic OS compared to healthy controls. Given the early age of onset and the extensive constitutional CNVs, we hypothesize that these genomic alterations are linked to susceptibility to OS. Here we investigate whether specific constitutional CNVs are related to susceptibility to sporadic OS and whether OS tumor CNAs arise via progression of constitutional CNVs in these patients. Blood derived DNA samples from patients with sporadic OS with wild-type germline p53 sequence and gene dosage were selected for analysis on Affymetrix GW6.0 arrays with paired pre-therapy tumor biopsies. Initial results from a discovery set of samples (n=43 pairs) reveal a copy number loss at 1q43, in a region that overlaps several genes that have a role in bone formation, microtubules and cytoskeletal organization. This loss was present in 43% of the blood-derived DNA samples and 44% of the tumor-derived samples, whereas this variant was noted in only 1.2% of controls. Furthermore, the germline 1q43 deletion correlates with poor survival of the OS patients (p=0.04, Long Rank). Analysis of an independent validation set (n=32 pairs) is currently underway to confirm the initial finding and further characterize specific constitutional CNVs among sporadic OS patients. The findings of this study will open new avenues for the discovery of novel loci implicated in susceptibility to OS with potential for improved diagnostic and prognostic options as well as further insight into disease pathogenesis.
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 1447. doi:1538-7445.AM2012-1447
Abstract 1449: Spicing up radiation treatment for prostate cancer
Authors: Venier Natalie A. , Colquhoun Alexandra J. , Loblaw Andrew , Fleshner Neil E. , Klotz Laurence H. , Venkateswaran Vasundara 
Published: August 2012

Abstract
Introduction and Objective: Radio-sensitizing agents sensitize cells to the lethal effects of ionizing radiation (IR). This permits use of lower doses of radiation to achieve equivalent cancer control thereby minimizing adverse effects to normal tissues. Given their lack of toxicity compounds occurring naturally in the diet make ideal potential radio-sensitizing agents. Capsaicin is the active compound chilli peppers. Traditionally capsaicin is used to treat chronic pain syndromes; however, recently evidence using in vitro prostate cancer (PCa) models describes its anti-carcinogenic potential. In our preliminary studies we have demonstrated the radio-sensitizing capacity of in PCa cells in vitro. Cells treated with capsaicin and/or IR to have increased expression of pro-apoptotic tumour-suppressor proteins p21 and p27 and reduced androgen-receptor. The objective of the present study is to assess the radio-sensitizing capacity in an in vivo model. Methods: Athymic nude mice were inoculated subcutaneously with human PCa (LNCaP) cells. Once xenografts reach 100mm3 forty animals will be randomized into 4 groups (15 /group); control (no treatment), capsaicin alone, ionizing radiation (IR) alone and capsaicin and IR. Treatments were administered over a two-week time period. Capsaicin (5 mg/kg/d) or vehicle was administered 3/week by gavage. RT will be delivered to animals in sterile cages as one fraction (6 Gray). Control animals were mock irradiated. Tumours were measured thrice weekly and volumes were calculated. Tumours were fixed and stained for pathological analyses and immunohistochemical evaluation. Results: There were no differences in food consumption or body weight of mice between groups. Two mice experienced mild to moderate inflammation of the stomach. No other toxicities were observed. Mice treated with capsaicin or IR alone had a significant reduction in tumour growth overtime (p &lt; 0.001). Mice treated with capsaicin and IR capsaicin had a reduction in the tumour volume greater than either capsaicin alone (p&lt;0.001) or radiation alone.(p&lt;0.03) We are currently investigating mechanism. Conclusion: These studies confirm the radio-sensitizing capacity of capsaicin in PCa xenograft model cells. Ongoing studies using are further delineating the mechanism of interaction of these treatment modalities.
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 1449. doi:1538-7445.AM2012-1449
Abstract 1453: The cannabinoid Win55, 212-2 enhances the response of breast cancer cells to radiation
Authors: Emery Sean M. , Sumner Evan T. , Lichtman Aron H. , Gewirtz David A. 
Published: August 2012

Abstract
Win55, 212-2 (Win2) is a full efficacy agonist for the endocannabinoid system, which is the target of Δ9-tetrahydrocannabinol (THC), the psychoactive compound in marijuana. Cannabinoids have demonstrated antiproliferative actions in many preclinical cancer models both in vitro and in vivo. The current studies were performed in the MCF-7, MDA-MB-231, or 4T1 breast cancer cell lines. Trypan blue exclusion was utilized as a measure of cell viability. Flow cytometry with propidium iodide was used for cell cycle analysis, while apoptosis and necrosis were assessed by Annexin V/PI staining. Win2, at concentrations of 4, 8 and 12μM, enhanced the antiproliferative effects of ionizing radiation (2, 4 and 8 Gy doses) in MCF-7 cells. The combination of Win2 and IR was also shown to be effective in MDA-MB-231 and 4T1 cells. This interaction was confirmed in vivo in 4T1 cells using 5mg/kg Win2 administered twice weekly in combination with one 10Gy dose of radiation. Win2 (8μM) for 24 hrs and 1 x 2Gy radiation was used for all subsequent experiments (Win/IR). Interestingly, neither THC nor the non-psychoactive cannabinoid, Cannabidiol, enhanced the response to radiation in MCF-7 cells, suggesting a possible drug-class specific effect. A time course study using Win/IR in MCF-7 cells suggested that Win2 and IR each alone induced growth arrest while the combination caused cell death. Cell cycle analysis indicated that at 24 hrs radiation alone (2 Gy) had no significant effect on cell cycle distribution; however, Win2 either alone or in combination with radiation produced a robust G1 accumulation. At 48 hrs, Win2 alone or in combination with radiation caused a significant increase in the subG1 population, implicating necrosis or apoptosis; however Annexin V/ PI staining was not consistent with either mode of cell death. The absence of apoptosis or necrosis lead us to believe that autophagy may be involved; however, the late autophagic inhibitor, Chloroquine (CQ), was unable to alter the effects of Win/IR, suggesting that autophagy is also not playing a primary role. Taken together, the absence of strong evidence for apoptosis, necrosis or autophagy suggests that the subG1 population could reflect necroptosis, and studies are underway to assess this possibility. Although the mechanisms of drug-radiation interaction remain to be defined, it is clear that Win2 does enhance the effects of radiation in breast cancer 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 1453. doi:1538-7445.AM2012-1453
Abstract 1455: Knock down of the aryl hydrocarbon receptor sensitizes human breast carcinoma cell lines to radio- and chemotherapy
Authors: Goode Gennifer D. , Eltom Sakina 
Published: August 2012

Abstract
Breast cancer is the most common cancer in North American women and is the second leading cause of cancer deaths in women today. Despite recent advances in treatment of breast cancer the development of chemo- and radio-resistance remains a major obstacle in treating advanced breast cancer. The aryl hydrocarbon receptor (AhR) is overexpressed and constitutively activated in several human breast carcinoma cell lines and the expression levels showed strong correlation with the degree of the tumor malignancy. In the current study, we evaluated the effect of reducing AhR expression on the chemo- and radio-sensitization of the MDA-MB231 human breast cancer cell line. We stably knocked down (KD) AhR expression in MDA-MB231 by using retroviral vectors expressing AhR-specific shRNA. Results show that reducing AhR expression enhanced radiation-induced apoptosis as shown by FITC-annexin V assay as well as significantly reducing cell clonogenic survival of MDA-MB231 cell line. In addition, knockdown of AhR alone has significantly impacted expression of genes regulating apoptotic pathways in these cells; increasing the expression of a number of pro-apoptotic genes while anti-apoptotic genes were down-regulated. Furthermore, the AhR-KD MDA-MB231 cells were sensitized to paclitaxol treatment; seen as an increase in the dose-dependent cytotoxicity compared to control cells. Our results suggest that reduction of AhR expression increases the chemo- and radio-sensitivity of MDA-MB231 breast cancer cell line. Therefore, AhR could be a novel target for enhancing efficacy of chemo and radiotherapy of breast 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 1455. doi:1538-7445.AM2012-1455
Abstract 1462: Targeting NAD+ biosynthesis combined with radiation to enhance cell death
Authors: Triest Baukelien Van , Zerp Shuraila F. , Floot Ben , Vens Conchita , Verheij Marcel 
Published: August 2012

Abstract
Background and purpose: APO866 is a highly specific non-competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the regulation of NAD+ biosynthesis. Inhibition of NAMPT reduces cellular NAD+ levels. Among NAD+ consuming enzymes are Poly(adenosine-diphosphate[ADP]-ribose)polymerases (PARPs) and Sirtuins. As a consequence, NAD+ is involved in numerous biochemical processes, including regulation of DNA repair, replication, transcription and apoptosis. APO866 is thought to preferentially target tumor cells because of their high NAD+ turnover rates and increased dependence on NAD+ as compared to normal cells. In the present study we investigated the cytotoxic effect of APO866 alone and in combination with radiation on tumor cells in vitro and in vivo. Results: APO866, in nanomolar concentrations, induces a time- and dose-dependent depletion of cellular NAD+ levels in a panel of human tumor cell lines (U937, J16, LNCaP, PC3 and A431). In vitro, under APO866-mediated reduced NAD+ conditions, solid tumor cell lines PC3 and LNCaP show besides a cytotoxic effect also a decrease in clonogenic survival in combination with ionizing radiation (Dose enhancement factor at 10% survival: 1.34 and 1.45 resp.), which was not caused by radiation-induced enhancement of dsDNA breaks as determined by γ-H2AX nuclear foci formation, nor by induction of apoptosis. In vivo experiments with PC3 xenografts, treated with the APO866/radiation combination, show the combination is more effective than APO866 or radiation treatment alone. The time to reach 300% of the initial tumor volume was in the control group 9.5 days, for APO866 treatment 28.6 days, radiation treatment 51.4 days and for the combined APO866/radiation treatment 76.6 days. Only the combination treatment caused complete initial growth regression. No significant toxicity was observed after any of these treatments. Tumors from animals treated with APO866 showed significant reduced NAD+ levels. Conclusion: APO866 treatment depletes NAD+ and enhances tumor cell kill in combination with radiation, in vitro and in vivo. Targeting NAD+ biosynthesis together with radiation is a promising strategy to enhance tumor response.
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 1462. doi:1538-7445.AM2012-1462