bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 818: Modulation of gene expression and cell cycle signaling pathways in Iressa-treated urinary bladder cancer in rats
Authors: Lu Yan , Liu Pengyuan , Grubbs Clinton , Lubet Ronald , You Ming 
Published: June 2012

Abstract
The EGFR inhibitor Iressa has demonstrated strong preventive efficacy in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) model of bladder cancer in the rat. To explore its antitumor mechanism, we implemented a systems biology approach to characterize gene expression and signaling pathways in rat urinary bladder cancers treated with Iressa. Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa and seven normal bladder epithelia were profiled using Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 down-regulated and 641 up-regulated genes in comparing bladder tumors vs. normal bladder epithelia. In addition, 178 genes were down-regulated and 96 genes were up-regulated when comparing control tumors vs. Iressa-treated tumors. Two coexpression modules that were significantly correlated with tumor status and treatment status were identified (r = 0.70, P = 2.80 × 10−15 (bladder tumor vs. normal bladder epithelium) and r = 0.63, P = 2.00 × 10−42 (Iressa-treated tumor vs. control tumor), respectively). Both tumor module and treatment module were enriched for genes involved in cell cycle processes. Twenty-four and twenty-one highly connected hub genes likely to be key drivers in cell cycle were identified in the tumor module and treatment module, respectively. Analysis of microRNA genes on the array chips demonstrated that tumor module and treatment module were significantly associated with expression levels of let-7c (r = 0.54, P = 3.70 × 10−8 and r = 0.73, P = 1.50 × 10−65 respectively). These results suggest that let-7c down-regulation and its regulated cell cycle pathway may play an integral role in governing bladder tumor suppression or collaborative oncogenesis and that Iressa exhibits its preventive efficacy on bladder tumorigenesis by up-regulating let-7 and inhibiting the cell cycle. The identified hub genes may also serve as pharmacodynamic or efficacy biomarkers in clinical trials of chemoprevention in human bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 818. doi:10.1158/1538-7445.AM2011-818
Abstract 82: Expression of MUC17, a marker of pancreatic cancer, is under the control of epigenetic modifications
Authors: Kitamoto Sho , Yamada Norishige , Yokoyama Seiya , Houjou Izumi , Higashi Michiyo , Goto Masamichi , Batra Surinder K. , Yonezawa Suguru 
Published: June 2012

Abstract
MUC17 glycoprotein is a membrane-associated mucin that is mainly expressed in the digestive tract. It has been reported that aberrant MUC17 expression is observed in pancreatic ductal adenocarcinomas (PDACs) and correlated with the malignancy potential.
In the present study, we provided the first report of the MUC17 gene expression through epigenetic regulation such as promoter methylation, histone modification and microRNA (miRNA) expression. To investigate DNA methylation status in the 5’flanking region of MUC17, MassARRAY analysis was performed on 10 cell lines. This method permits the high-throughput identification of the methylation sites and their semi-quantitative measurement. Near the transcriptional start site (−179 to +52), a high level of CpG methylation was observed in MUC17-negative/low cells (e.g., Panc-1), whereas that of MUC17-positive cells (e.g., AsPC-1) was low. We also examined the relationship between DNA methylation and histone modification in MUC17 expression by ChIP assay, resulting the presence of dimethyl-H3-K9 in cells with no or low MUC17 was confirmed, whereas histone H3-K9 was more highly acetylated in MUC17-positive cells than in cells with no or low MUC17. These results suggest that the combination of DNA methylation and histone H3-K9 modification contribute to MUC17 expression. Futhermore, in the result of miRNA microarray analysis, we revealed that the five potential miRNAs are existed for the post-transcriptional regulation of MUC17.
Our findings indicate that MUC17 is regulated tightly through epigenetic manners including DNA methylation, histone modification and miRNA regulation and also suggest the possible functional importance of MUC17 in both physiological and pathological conditions. Furthermore, for the clinical aspect, the DNA hypomethylation was also observed in patients with PDAC. This may be of importance for the diagnosis of carcinogenic risk and the prediction of outcomes for cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 82. doi:10.1158/1538-7445.AM2011-82
Abstract 820: The synthetic triterpenoids, CDDO-methyl ester and CDDO-ethyl amide, and the histone deacetylase inhibitor vorinostat delay carcinogenesis in a transgenic model of estrogen receptor-negative breast cancer
Authors: Tran Kim M. , Sporn Michael B. , Liby Karen 
Published: June 2012

Abstract
The incidence of estrogen receptor (ER)-positive breast cancer has declined over the last several years; however, there has been no change in the incidence of ER-negative breast cancer. Novel drugs and drug combinations are needed for the chemoprevention of ER-negative breast cancer. We show that the methyl ester or ethyl amide derivatives of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-ME and CDDO-EA, respectively) and the histone deacetylase inhibitor Vorinostat (suberoylanilide hydroxamic acid (SAHA)) delay the formation of ER-negative mammary tumors in MMTV-Polyoma Middle T (PyMT) mice. Female PyMT mice were fed control diet, CDDO-ME (50mg/kg diet), CDDO-EA (400mg/kg diet), and SAHA (250mg/kg diet), or the combinations of each triterpenoid and SAHA, beginning at 4 weeks of age. To detect initial tumor development, mice were palpated twice a week. CDDO-ME, CDDO-EA, and SAHA each significantly delayed the development of ER-negative tumors, by an average of 4.3 weeks (p &lt; 0.001), 1.2 weeks (p &lt; 0.05), and 2 weeks (p &lt; 0.001), respectively, compared to the control group. The combination of either CDDO-ME or CDDO-EA with SAHA was significantly more potent than the individual drugs at delaying tumor development, with an average of a 5.75 (p &lt; 0.001) and 5.83 (p &lt; 0.001) week delay, respectively, compared with the control group. Additionally, CDDO-ME and SAHA significantly improved survival, with an average improvement of 5.2 weeks (p &lt; 0.001) and 1.5 weeks (p &lt; 0.05), respectively, compared to the control group. As a single agent, CDDO-EA had no significant effect on survival; however, current studies suggest that the combination of CDDO-EA and SAHA may synergistically improve survival in PyMT mice. To elucidate the mechanisms responsible for tumor delay and improvement in survival, primary epithelial cells were isolated from mammary tumors of female PyMT mice. Treatment with CDDO-ME at nanomolar concentrations resulted in a significant repression of the biomarker cyclin D1 and the induction of the cell cycle regulator p21 at the protein level. Current studies are investigating additional mechanisms of action of CDDO-ME, CDDO-EA, and SAHA and will be presented. This study shows that as single agents, CDDO-ME, CDDO-EA, and SAHA delay ER-negative mammary tumorigenesis and also synergize when used in combination for prevention.
This work was supported by the Breast Cancer Research Foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 820. doi:10.1158/1538-7445.AM2011-820
Abstract 839: A novel Gemini vitamin D analog represses a stem cell marker CD44 and its variant CD44v6 and inhibits CD44-Met signaling in breast cancer
Authors: So Jae Young , Smolarek Amanda K. , Maehr Hubert , Uskokovic Millan , Cai Li , Liu Fang , Suh Nanjoo 
Published: June 2012

Abstract
CD44, a transmembrane glycoprotein that is involved in cell-cell interaction and cell adhesion, has been recognized as a key cell-surface marker for breast cancer stem cells. The CD44 positive breast cancer cells are enriched in residual breast tumors after conventional therapies, suggesting CD44 as an important therapeutic target to block the recurrence of breast cancer. To investigate CD44 expression during tumor progression, we used the CD44 overexpressing MCF10DCIS.com cell line as a model for breast cancer progression. We injected MCF10DCIS.com cells into immunodeficient mice and analyzed the resulting tumors after 1, 2, 3, 4 and 5 weeks from cell injection. MCF10DCIS.com cells formed ductal carcinoma in situ like lesion by week 2 and invasive tumor lesions by week 3. CD44 proteins were highly expressed in the membrane of epithelial cells in mammary tumors, suggesting that human MCF10DCIS.com cell line might be a useful model for studying therapeutic agents targeting CD44 positive breast cancer cells. We previously reported that a Gemini vitamin D analog, BXL0124, significantly down-regulated the expression level of CD44 in MCF10DCIS.com cells in vitro and in DCIS xenograft tumors. In the present study, we demonstrated that BXL0124 strongly repressed the protein expression level of two alternative splicing variants of CD44, CD44v3 and CD44v6, in MCF10DCIS.com xenografted tumors. Because these CD44 variants are closely associated with breast cancer growth and invasion, the repression of CD44 variants by BXL0124 in MCF10DCIS.com xenograft tumors may contribute to the inhibitory effect of BXL0124 on tumor growth and invasion. We further investigated the effect of BXL0124 on the Met receptor, which is known to interact with CD44v6 for its downstream signaling transduction to control cancer invasion and metastasis. The treatment with BXL0124 decreased the protein expression level of CD44v6 and inhibited hepatocyte growth factor (HGF)-induced Met signaling in cultured MCF10DCIS.com cells. In the CD44 promoter assay, mutation of p53 binding site in the CD44 promoter abolished the repression of CD44 transactivation by BXL0124, indicating that p53 is necessary for the repression of CD44 by BXL0124. In conclusion, BXL0124 repressed CD44 expression in a p53-dependent manner and inhibited CD44-Met signaling in MCF10DCIS.com cells. Our study suggests the Gemini vitamin D analog, BXL0124, is a potentially useful agent in inhibiting breast cancer by targeting CD44 expressing cancer stem cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 839. doi:10.1158/1538-7445.AM2011-839
Abstract 84: OGDHL is epigenetically silenced and suppresses growth in human cervical cancer
Authors: Sen Tanusree , Ravi Rajani , Wu T.-C. , Sidransky David , Hoque Mohammad Obaidul 
Published: June 2012

Abstract
Despite the significant benefits conferred by screening for cervical cancer, cervical cancer is responsible for 190,000 deaths annually worldwide and the leading cause of cancer mortality in women in developing countries. Thus, there is a great need for improvements in cervical screening and targeted therapies. Such improvements depend, however, on a better understanding of the molecular biology of cervical neoplasia.
The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Recently, in a human genome-wide survey, we identified oxoglutarate dehydrogenase-like (OGDHL) gene as a cancer specific methylated gene located on chromosome 10q11.23. Oxoglutarate dehydrogenase (OGDH) is the first and rate-limiting component of the multienzyme OGDH complex (OGDHC) whose malfunction is associated with neurodegeneration. The essential role of this complex is in the degradation of glucose and glutamate. OGDHL is down-regulated by promoter hypermethylation in cervical cancer cell lines and cervical cancer specific methylation was observed with 100% specificity. These properties suggest an important tumor suppressor role for OGDHL, yet direct genetic evidence of a tumor suppressor function for OGDHL is lacking and the molecular mechanism(s), through which OGDHL exerts its tumor suppressor functions, has not been shown.
Here, we report that restoration of OGDHL expression in cervical cancer cells lacking endogenous OGDHL expression suppressed cell proliferation and invasive phenotypes in in vitro and colony formation in soft agar. On the other hand, knockdown of OGDHL expression in cervical cancer cells expressing endogenous OGDHL promoted cell proliferation, invasive phenotypes and several malignant behaviors. Mechanistic analysis indicated that OGDHL up-regulation increases the production of reactive oxygen species (ROS) leading to apoptosis through down-regulation of AKT signaling cascade. Conversely, silencing OGDHL stimulated the signaling pathway via increased phosphorylation of PI3K, AKT and ERK1/2; it was also associated with phosphorelation of NFκβ, a molecule when activated can cause the cells to develop survival advantage, resist cell death and resist chemotherapy drugs.
Taken together, these data suggest that inactivation of OGDHL, an isoform of the 2-oxoglutarate dehydrogenase, can contribute to cervical tumorigenesis via activation of the AKT signaling pathway and support the therapeutic potential for this protein.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 84. doi:10.1158/1538-7445.AM2011-84
Abstract 860: Benzyl isothiocyanate inhibits oncogenic actions of leptin in human breast cancer cells by suppressing activation of signal transducer and activator of transcription 3
Authors: Kim Su-Hyeong , Nagalingam Arumugam , Saxena Neeraj K , Singh Shivendra V , Sharma Dipali 
Published: June 2012

Abstract
Obesity is a well-established risk factor for breast cancer progression and molecular effects of obesity are mediated by adipocytokine, leptin. Considering the important role of leptin in breast cancer growth and metastasis, novel strategies to antagonize biological effects of this adipocytokine are much desired. We showed previously that benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g., gardencress), confers significant protection against mammary carcinogenesis in a transgenic mouse model (MMTV-neu). The BITC-mediated prevention of mammary cancer development in MMTV-neu mice correlated with reduced cell proliferation, increased apoptosis, and tumor infiltration of T cells. The present study provides first evidence for efficacy of BITC against oncogenic effects of letpin. BITC-treatment circumvented leptin-induced clonogenicity and anchorage-independent growth of MDA-MB-231 (an estrogen-independent cell line with mutant p53) and MCF-7 human breast cancer cells (an estrogen-responsive cell line with wild-type p53) at pharmacologic doses. Leptin-stimulated migration and invasion of these cells was also inhibited significantly in the presence of BITC. Analysis of the underlying molecular mechanisms revealed that BITC-treatment suppressed leptin-induced phosphorylation of signal transducer and activator of transcription 3 (Stat3) and cyclin D1 transactivation. BITC-treatment efficiently inhibited Stat3 recruitment to the cyclin D1 promoter in a chromatin immunoprecipitation analysis. Furthermore overexpression of constitutively active Stat3 imparted significant protection against BITC-mediated inhibition of cyclin D1 transactivation whereas RNA interference of Stat3 resulted in a significant increase in BITC-mediated inhibition of cyclin D1 transactivation in the presence of leptin. BITC-mediated inhibition of MDA-MB-231 xenograft growth correlated with a decrease in level of phospho-Stat3. These studies indicate that Stat3 plays an important role in BITC-mediated inhibition of leptin-induced cyclin D1 transactivastion. Taken together, these data show that BITC treatment can inhibit the oncogenic actions of leptin via blocking its downstream signaling molecule, Stat3.
In conclusion, BITC could potentially be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels. This work was supported in part by the USPHS grants NCI-RO1 CA129347 (to SVS), NIDDK-K01DK076742 and R03DK089130 (to NKS), NCI-R01CA131294 and NCI-R21 CA155686 (to DS).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 860. doi:10.1158/1538-7445.AM2011-860
Abstract 862: Expression of the fat-1 gene retards the growth of cervical cancer cells in vitro and in vivo
Authors: Lim Kyu , Song Kyoung-Sub , Shin Soyeon , Kim Nayeong , Jeong Soyeon , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Kwon Hyun-Joo , Park Hae-Duck , Dai Yifan , Park Jong-Il , Park Seung-Kiel , Kweon Gi-Ryang , Yoon Wan-Hee , Hwang Byung-Doo , Jing Kaipeng 
Published: June 2012

Abstract
Omega 3-polyunsaturated fatty acids (ω3-PUFAs) are known to inhibit proliferation of cancer cells; in contrast, ω6-PUFAs promote the growth of cancer cells. The fat-1 gene of the Caenorhabditis elegans encodes a ω3-desaturase that catalyzes the conversion ω6-PUFAs to ω3-PUFAs and then increases the amount of ω3-PUFAs. The objective of this study is to examine the effect of fat-1 gene expression on HeLa and SiHa human cervical cancer cells. Fat-1 gene stable cell lines (f-HeLa and f-SiHa) were established from HeLa and SiHa cells, respectively. The expression of fat-1 gene significantly inhibited cervical cancer cell proliferation and f-HeLa cells showed an increase in the proportion of cells in G2/M phase comparing with the cells expressing the control vector (c-HeLa). In addition, when treating HeLa cells with docosahexaenoic acid (DHA), an enhanced proportion of cells in the G2/M phase was also observed, indicating that fat-1 gene inhibited cervical cancer cell proliferation by inducing a G2/M phase cell-cycle arrest. Furthermore, transwell migration assay for invasion showed a reduction of cell migration in the f-HeLa cells when compared with the c-HeLa cells. Finally, the growth of f-HeLa cells in vivo was significantly reduced comparing with the c-HeLa cells when inoculated into nude mice. Taken together, these results suggest that the expression of fat-1 gene prevents cervical tumor growth and indicate a cancer therapeutic approach of the ω3-PUFAs. Therefore, a stable cell line of fat-1 gene is useful to study the anti-cancer effects of ω3-PUFAs.
[This research was supproted by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (E00026 and R13-2007-020-01000-0)].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 862. doi:10.1158/1538-7445.AM2011-862
Abstract 891: The association of single nucleotide polymorphisms in folate metabolism genes with hypermethylation patterns in smokers at high risk for lung cancer
Authors: Flores Kristina G. , Stidley Christine A. , Picchi Maria A. , Mackey Amanda J. , Byers Tim , Berwick Marianne , Belinsky Steven A. , Leng Shuguang 
Published: June 2012

Abstract
Hypermethylation of promoter regions serve as potential biomarkers for the early detection of lung cancer. Because folate metabolism is necessary for nucleotide synthesis and DNA methylation reactions, that when perturbed, may both contribute to the development of cancer, hypermethylation of promoter regions in folate metabolism genes may be particularly important to explore. Dietary folate was recently found to protect against gene promoter hypermethylation patterns. This study investigated the association of functional and haplotype tagging single nucleotide polymorphisms (SNPs) in folate metabolism genes with promoter hypermethylation in sputum cell DNA from a cohort of current and former smokers (n=937). This cohort was a subset of the Lovelace Smokers’ Cohort of approximately 2000 high risk current and former smokers who were non-Hispanic white and for whom a complete methylation panel was obtained. Methylation panel status from a 12 gene panel was dichotomized into high and low methylation based on a cutoff of the number of genes methylated (&gt; = 3 genes for women and &gt; = 4 genes for men were categorized as high). Lymphocyte DNA was interrogated on a 96 SNP Illumina Goldengate platform. A SNP in the cystathionine-beta synthase gene (CBS), that converts homocysteine to cystathionine, was found to be significantly associated with gene promoter hypermethylation. Analyses used logistic regression and adjusted for multiple comparisons. There was an interaction between gender and CBS (p&lt;0.0001), so we conducted a stratified analysis by gender. Males with the variant allele had an increased risk of methylation (OR = 3.61; 95% CI: 1.71, 7.64); p&lt;0.001) and females with the variant allele had a decreased risk for methylation (OR = 0.64; 95% CI: 0.40, 1.00; p=0.05). A 20% reduction in CBS gene transcription was seen in bronchial epithelial cells heterozygous for the CBS variant allele compared to cells without the variant allele but was not statistically significant. Epidemiological studies have shown that men have higher levels of homocysteine compared to women but the mechanisms regulating this difference are not known. This study shows that a SNP in the CBS gene is associated with methylation patterns in smokers at high risk to develop lung cancer and differs by gender. This work may further help to elucidate the differences in lung cancer risk by gender.
Grant Support: This work is supported by K01CA128823 NCI and R01CA097356 NCI
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2011-891