bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4001: SOX7 is a potential tumor suppressor in breast cancer
Authors: Stovall Daniel B. , Wan Meimei , Zhang Qiang , Liu Gaifang , Cao Paul , Miller Lance D. , Liu Wennuan , Xu Jianfeng , Sui Guangchao 
Published: August 2012

Abstract
Among U.S. women, breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths. Both epigenetic silencing and genetic deletion of tumor suppressors are critical for the development and progression of breast cancer. The SOX (Sex-determining region Y-box) genes encode a family of over 20 transcription factors, including SOX7. The SOX7 gene is located on chromosome arm 8p and is deleted in a number of human cancers, including breast cancer. Previously, SOX7 has been demonstrated to be down-regulated in human tissues of prostate and colon cancers and its ectopic expression inhibits proliferation and increase apoptosis in prostate and colon cancer cell lines. However, the functional role of SOX7 in breast cancer has not yet been reported. Our studies revealed a significant correlation between SOX7 transcript levels and clinical outcome in gene array data from an international meta-cohort of 674 breast cancer patients. Consistently, we observed that SOX7 mRNA levels and protein expression are down-regulated in multiple breast cancer tissues and breast cancer cell lines compared to adjacent normal tissue and non-tumorigenic cells, respectively. Further, we have observed that the SOX7 promoter is hyper-methylated in breast cancer cell lines compared to non-tumorigenic breast cells, and that inhibition of SOX7 methylation results in an increase in SOX7 mRNA. Importantly, shRNA-mediated silencing of SOX7 conferred a growth advantage to non-tumorigenic breast cells, while induced ectopic SOX7 expression inhibited proliferation and migration of breast cancer cells. Overall, our data suggest that SOX7 may act as a novel tumor suppressor in 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 4001. doi:1538-7445.AM2012-4001
Abstract 4004: P21-activated kinases (PAKs) are novel therapeutic targets in human breast cancer
Authors: Ong Christy , Jubb Adrian , Haverty Peter , Zhou Wei , Lyle Karen , Harris Adrian , Belvin Marcia , Friedman Lori , Koeppen Hartmut , Hoeflich Klaus P. 
Published: August 2012

Abstract
P21-activated kinases (PAKs) are important mediators of Rac and Cdc42 GTPase function as well as pathways required for Ras-driven tumorigenesis. PAKs have been implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion and actin cytoskeleton organization. To better understand the role of PAK1 and PAK4 in breast tumorigenesis, genomic copy number, mRNA and protein expression were determined for a panel of 291 human breast adenocarcinomas and loss-of function was assessed in cell lines using genetic and pharmacologic approaches. Interestingly, PAK1 genomic amplification at 11q13 was prevalent in luminal breast cancer and PAK1 levels in early ductal carcinoma in situ (DCIS) samples was similar to that of primary adenocarcinoma suggesting that PAK1 dysregulation could be an early event in some breast cancers. PAK1 protein expression in adenocarcinoma was associated with lymph node invasion and further increased expression was observed in metastatic tumors. In addition, primary and secondary (28 local recurrences, 56 metastases) adenocarcinomas from a total of 86 patients (81 with matching samples) were evaluated for PAK1 and PAK4 expression to determine modulation of these kinases following adjuvant hormone therapy. Breast cancer cell lines with PAK1 genomic amplification rapidly underwent caspase activation and apoptosis following inhibition of this kinase. Together, our results provide evidence for dysregulation of PAK1 in breast cancer and a role for PAK1 in cellular survival and proliferation in this indication.
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 4004. doi:1538-7445.AM2012-4004
Abstract 402: Plasticity of tumor associated macrophages in a metastatic melanoma model in the mouse
Authors: Gal Annamaria , Tapmeier Thomas T. , Muschel Ruth J. 
Published: August 2012

Abstract
Macrophages acquire different functional traits, with the pro-inflammatory, classically activated M1 and the tissue-repair, alternatively activated M2 phenotypes the best characterized to date. Tumor-associated macrophages (TAMs) have been described as alternatively activated and exert pro-tumoral activity. We investigated TAMs isolated from subcutaneous tumors and experimental lung metastases at an early (72 h) and late (3 wk) stage within a B16F10 mouse melanoma model. The macrophages were characterized according to their expression of genes, surface markers and secreted factors. Interestingly, the mRNA profile revealed both M1- and M2-associated gene expression in macrophages derived from s.c. melanoma, including Cxcl9, Cxcl11, Il-1a, Nos2, and Retnla (FIZZ-1), Arg-1 and Fn1, respectively. In early pulmonary metastases, we found that macrophages also expressed both pro-inflammatory (Il1b, Il12b, Ccl2), and anti-inflammatory (Ccl17 and Ccl22) cytokines and chemokines and other M1- and M2-associated genes, such as Cd40, Cd86, and Il27ra and Itgax (Cdd11c), respectively. Macrophages from late stage lung metastases displayed predominantly alternatively activated characteristics with Arg1, Retnla and Fn1 expression, but pro-inflammatory genes, such as Ccl2, Il1b and Cxcl10 were also induced/upregulated. We therefore suggest an intermediate phenotype of TAMs which does not fit the orthodox M1/M2 paradigm. To describe the mechanism by which macrophages are recruited to pulmonary metastases, we investigated chemokine receptor expression of macrophages infiltrating the lung. While Ccr2 was expressed at high level in macrophages associated with both the control and B16F10 metastases bearing lung, we found that Ccr1 and Ccr5 expression was induced after tumor cell challenge. The secretion profile of B16F10 cells revealed CCL5 (RANTES), a ligand for these receptors, secreted at high level, which suggests that CCL5 attracts macrophages to lung metastases via CCR1 and CCR5. The effect of anti-CCL5 antibody treatment, and s.c melanoma growth and pulmonary metastasis development in CCR1-/- and CCR5-/- mice will be discussed.
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 402. doi:1538-7445.AM2012-402
Abstract 4027: Regulation of p16INK4A and TGF-beta by DNA hydroxymethylation in glioblastoma multiforme
Authors: Popkie Anthony P. , deCarvalho Ana C. , Scott Stephanie B. , Eugster Emily E. , Monsma David , Davidson Paula J. , Dawna Dylewski , Mooney Marie R. , Monks Noel R. , Mikkelsen Tom , Webb Craig P. 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most prevalent form of primary brain cancer in adults. Cancer stem cells (CSCs) are thought to drive the growth and metastasis of tumors, and are readily isolated from GBM patient tumors. These GBM CSCs are maintained under serum-free conditions in neurosphere media, and form tumors upon orthotopic injection in mice. However, when grown in the presence of serum, GBM CSCs undergo morphological changes, have reduced proliferation, exhibit loss of stem cell markers, and have reduced tumorigenicity following orthotopic implantation into the brains of immune compromised mice. Upon return to serum-free neurosphere media, these GBM CSCs revert to neurospheres. We set out to define the transcriptional incongruities between these culture condition-dependent states, and the underlying epigenetic changes which regulate these differences in gene expression. Although genetic alterations in cancer are irreversible, epigenetic changes are inherently reversible, and we hypothesize that the plasticity between culture condition-dependent states is mediated by epigenetic regulation of genes relevant to the ability of these cells to form tumors. Recently, a novel epigenetic mark, 5-hydroxymethylcytosine (5hmC), has been shown to be enriched at regulatory elements within polycomb target genes in embryonic stem cells, and is frequently found at genes that are involved in the maintenance of stem cells. We found that 5hmC levels of several polycomb target genes, including p16INK4A and several components of the TGF-beta pathway involved in epithelial to mesenchymal transition (EMT), are altered in neurospheres compared to CSCs cultured in serum. Loss of p16INK4A expression has recently been associated with increased CSC abundance in breast cancer, and our results suggest that a similar trend exists in GBM. Furthermore, our results suggest that 5hmC is involved in the regulation of polycomb target genes in CSCs, including p16INK4A and components of the TGF-beta pathway. These findings implicate 5hmC in the maintenance of CSCs and regulation of EMT.
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 4027. doi:1538-7445.AM2012-4027
Abstract 4029: Enhanced chemosensitivity of estrogen receptor-α (ERα)-negative breast cancer through soybean genistein-induced epigenetic reactivation of ERα
Authors: Li Yuanyuan , Tollefsbol Trygve 
Published: August 2012

Abstract
Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and has a poor prognosis due to the lack of estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown. In our current studies, we found that GE can reactivate ERα expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERα-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERα-dependent cellular responses to activator 17β-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERα promoter thereby contributing to ERα reactivation. The global enzymatic activities for HDACs and DNA methyltransferases (DNMTs) mediated by GE were altered to favor ERα up-regulation. Consistently, dietary GE significantly reduced the growth of ERα-negative mouse xenograft tumors due at least in part to ERα reactivation. The combination of GE with TAM had more prominent effects on delaying tumor growth than either treatment alone. Collectively, our studies suggest that soybean genistein can epigenetically restore ERα expression, which in turn increases TAM-dependent anti-estrogen chemosensitivity. The results from our studies revealed a novel chemotherapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ERα-negative breast cancer which will provide more effective options in breast cancer therapy.
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 4029. doi:1538-7445.AM2012-4029
Abstract 4034: The role of CYP33 in MLL target gene repression
Authors: Poppen Steven , Diaz Manuel 
Published: August 2012

Abstract
This study further elucidates the role of CYP33 in gene transcription by studying the effects of CYP33 overexpression and siRNA-mediated down-regulation on the expression of MLL target genes such as c-MYC, p21, p27, and HOXA9. CYP33 is a cis-trans prolyl isomerase (PPIase) which mediates repression of HOX gene expression after binding to the 3rd PHD finger of MLL through its own RRM domain. Upon binding to MLL, CYP33 increases recruitment of HDAC to the MLL repression domain which in turn leads to deacetylation of histone H3. This ultimately causes repression of MLL target genes (Xia et al. 2003). Chromosomal translocations involving the MLL gene (Mixed Lineage Leukemia) can lead to the production of fusion proteins with any of more than 60 different partner proteins and is implicated in the initiation of leukemia. Expression of MLL fusion proteins leads to increased expression of MLL target genes such as HOXA7, HOXA9 and MEIS1 (Hess et al., 2010). MLL-fusion proteins lack the 3rd PHD finger and therefore, lose their ability to bind CYP33; in the presence of these fusion proteins CYP33 can no longer repress MLL target genes. A mutation in CYP33's PPIase domain, leads to an enzymatically inactive CYP33 which can still bind to MLL. Upon overexpression of MLL and CYP33, HDAC is recruited to the MLL complex, as demonstrated by co-immunopreciptiation. However, when the CYP33 PPIase mutant is overexpressed, the lack of PPIase activity prevents the recruitment of HDAC to MLL. As a consequence the chromatin retains the acetylation mark on histone H3 and, although the CYP33 PPIase mutant binds MLL, no repression of MLL target genes is observed. Conversely, upon knockdown of wild-type CYP33, MLL target gene expression and H3K27Ac are increased. This study aids in the understanding of how MLL and CYP33 modulate gene function and helps to identify some of the mechanisms involved in hematopoietic development and leukemia.
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 4034. doi:1538-7445.AM2012-4034
Abstract 4036: Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing
Authors: Basseres Daniela S. , D'Alò Francesco , Yeap Beow Y. , Gonzalez David A. , Yasuda Hiroyuki , Meyerson Matthew , Kobayashi Susumu , Tenen Daniel G. , Halmos Balazs , Costa Daniel B. 
Published: August 2012

Abstract
PURPOSE: We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC). METHODS: A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay. RESULTS: Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p=0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p&lt;0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173, 55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9-3.1; p=0.122).CONCLUSIONS: Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets.
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 4036. doi:1538-7445.AM2012-4036
Abstract 4040: Silence of miR-203 by promoter methylation in endometrial cancer
Authors: Huang Yi-Wen , Rader Janet S. , Stoner Gary D. , Goodfellow Paul J. , Huang Tim H-M. 
Published: August 2012

Abstract
MicroRNAs (miRNAs), a class of small non-coding RNAs, play important roles in cancer development by perturbing the expression of target genes. DNA methylation, a well-studied epigenetic event, also influences gene expression and aberrant methylation is frequently observed in cancer. We previously reported a new paradigm in which hypermethylation-mediated silencing of a miRNA de-repressed its oncogenic target in cancer cells. SOX4, an oncogene, was found to be overexpressed in endometrial cancer, partly because of hypermethylation of miR-129-2. Herein, thirteen additional miRNAs targeting on the 3′-end of untranslated regions of SOX4, and encompassing CpG islands, were identified using computational analysis. Hypermethylation of eight of the thirteen miRNAs was detected in at least two of seven endometrial cancer cell lines. miR-203 was selected for further analysis because this locus was predominantly hypermethylated in endometrial cancer cell lines, but not in normal endometrium. miR-203 expression can be reactivated by pharmacologic induction of DNA demethylation and histone acetylation, indicating that the loss of miR-203 expression is associated with promoter hypermethylation in endometrial cancer. Restoration of miR-203 by cell transfection decreased SOX4 expression and reduced proliferation of endometrial cancer cells. To confirm these in vitro findings in primary endometrial tumors, specimens from two cohorts were analyzed for miR-203 methylation by quantitative pyrosequencing or MassARRAY. In one cohort, miR-203 was significantly hypermethylated in endometrial tumors (n=31), but not in adjacent or un-related normal (n=18) specimens. Methylation of this locus is related to lymphatic and vascular invasion. In the other cohort, increased methylation was observed in primary tumors (n=114), but not in normal controls (n=22). Hypermethylation of miR-203 was positively associated with MLH1 methylation and MSI status. In conclusion, we present an emerging phenomenon that epigenetic silencing of multiple miRNAs could lead to overexpression of a single oncogene in endometrial cancer. This work is supported, in part, by NIH grants U54 CA113001 (THH) and P50 CA134254 (PJG, THH).
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 4040. doi:1538-7445.AM2012-4040
Abstract 4041: Identification of GNG7 as an epigenetically silenced gene in head and neck cancer by gene expression profiling
Authors: Demokan Semra , Chuang Alice Y. , Chang Xiaofei , Khan Tanbir , Smith Ian M. , Pattani Kavita M. , Dasgupta Santanu , Begum Shahnaz , Khan Zubair , Liegeois Nanette J. , Westra William H. , Sidransky David , Koch Wayne , Califano Joseph A. 
Published: August 2012

Abstract
Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. Aberrant hypermethylation in the promoter region of some known or putative tumor suppressor genes occurs frequently during the development of various cancers including head and neck squamous cell carcinoma (HNSCC). In this study we used an expanded mRNA expression profiling approach followed by microarray expression analysis to identify epigenetically inactivated genes in HNSCC. Two HNSCC cell lines were treated with 5-aza-2′-deoxycytidine followed by microarray analysis to identify epigenetically silenced genes in HNSCC. 1960, 614, and 427 genes were upregulated in HNSCC cell lines JHU-012, JHU-011 and the combination of both cell lines, respectively. HNSCC tumor and normal mucosal samples were used for gene profiling by a 47K mRNA gene expression array and we found, 7140 genes were downregulated in HNSCC tumors compared to normal mucosa as determined by microarray analysis and were integrated with cell line data. Integrative analysis defined 126 candidate genes, of which only seven genes showed differentially methylation in tumors and no methylation in normal mucosa after bisulfite sequencing. After validation by QMSP, one gene, GNG7, was confirmed as being highly methylated in tumors and unmethylated in normal mucosal and salivary rinse samples demonstrating cancer-specific methylation in HNSCC tissues. TXNIP and TUSC2 were partially methylated in tumors and normal salivary rinses but unmethylated in normal mucosa. We concluded GNG7 as a highly specific promoter methylated gene associated with HNSCC. In addition, TXNIP and TUSC2 are also potential biomarkers for HNSCC.
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 4041. doi:1538-7445.AM2012-4041
Abstract 4043: Loss of imprinting of KCNK9 in breast cancer
Authors: Skaar David A. , Seewaldt Victoria L. , Gould Michael N. , Jirtle Randy L. 
Published: August 2012

Abstract
KCNK9 (TASK-3) encodes a two-pore potassium channel that functions in tumor growth and survival. The potassium channel function is necessary for tumor proliferation and survival, by enhancing resistance to hypoxia and apoptosis. KCNK9 overexpression is observed in melanoma, colorectal cancer, and breast and brain tumors, but with no associated mutations found. Rather, the overexpression is often the apparent result of gene amplification of KCNK9, but any other mechanism that increases expression would presumably have a similar effect on tumorigenesis. This importance of gene dosage and expression levels is particularly relevant, as KCNK9 has been demonstrated to be a maternally expressed imprinted gene, which, in effect, reduces copy number. Monoallelic expression of KCNK9 was originally found in brain tissue, but our work has found that it is also imprinted in breast tissue. Thus, we hypothesized that loss of imprint control would be similar to a gene duplication, increasing the effective copy number, and therefore KCNK9 gene expression. To study the regulation of KCNK9 imprinting in tumors, we have screened for differentially methylated regions that may function as imprint control regions (ICRs), and examined the expression status of KCNK9 in breast tumor samples relative to the methylation state of the putative ICRs. Approximately 40-50% of breast tumor samples analyzed show loss of imprinting, seen as expression of both alleles of an exonic polymorphism. Additionally, loss of methylation at a putative ICR upstream of the transcription start site is observed in combination with loss of imprint regulation. This correlated loss of methylation and imprint control is seen most commonly in tumors of the “triple negative” subtype - tumors negative for expression of estrogen receptor, progesterone receptor, and HER2/neu. These novel findings regarding KCNK9 imprint regulation and its disruption in a subset of tumors may lead to new approaches in diagnosis and targeted therapy 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 4043. doi:1538-7445.AM2012-4043