bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5578: Breast cancer cell growth regulatory mechanisms of tamoxifen metabolites
Authors: Thomas T. , Hsu Huichen , Yang PingAr , Hyvonen Mervi T. , Keinanen Tuomo A. 
Published: May 2015

Abstract
The proliferation of estrogen receptor alpha (ERalpha)-positive breast cancer cells is stimulated by estradiol. Tamoxifen [(Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine] is the most commonly used endocrine treatment for ERalpha-positive breast cancer in pre- and post-menopausal women. Tamoxifen is metabolized to 4-hydroxytamoxifen and endoxifen. ICI 182780 (Faslodex or Fulvestrant) is a pure antiestrogen targeted to the ERalpha. We investigated the effects of endoxifen and 4-hydroxytamoxifen on ERalpha-positive MCF-7 breast cancer cells using cell growth assay, oncogene expression and polyamine regulatory pathways. Polyamines are ubiquitous cellular components and are essential for cell growth and differentiation. Treatment of cells for 1-5 days with 4 nM estradiol increased cells number, whereas the addition of endoxifen, 4-hydroxytamoxifen or ICI 182780 in combination with estradiol suppressed cell growth in a concentration- and time-dependent manner. Real time quantitative polymerase chain reaction (RT-qPCR) experiments showed that the addition of 4 nM estradiol to MCF-7 cells increased the expression of c-myc, c-fos and Tiff1 genes significantly, while the addition endoxifen, 4-hydroxytamoxifen, or ICI 182780 suppressed estradiol-mediated increase in gene expression. Polyamine biosynthetic enzymes were also affected by tamoxifen metabolites. Estradiol increased the activities of the polyamine biosynthetic enzyme, ornithine decarboxlase (ODC) and S-adenosylmethionine decarboxlase (AdoMetDC), whereas the antiestrogens suppressed ODC and AdoMetDC activities in a concentration- and time-dependent manner. However, these agents had little effect on the activity of the polyamine catabolic enzyme, spermidine/spermine N1-acetyl transferase (SSAT). The change in biosynthetic enzyme activities was reflected in polyamine pools, as decreased putrescine and spermidine levels. There was no significant change in spermine level. These results suggest that the mechanism of action of tamoxifen metabolites involves multiple cell growth regulatory pathways. In addition, endoxifen can act as an antiestrogen and suppress cell growth stimulatory effects of estradiol on ERalpha-positive breast cancer cells in a manner similar to that of ICI 182780.
Note: This abstract was not presented at the meeting.
Citation Format: T. Thomas, Huichen Hsu, PingAr Yang, Mervi T. Hyvonen, Tuomo A. Keinanen. Breast cancer cell growth regulatory mechanisms of tamoxifen metabolites. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5578. doi:10.1158/1538-7445.AM2014-5578
Abstract 5591: Simultaneous isolation and quantification of circulating exosomes for cancer biomarker discovery
Authors: Kanwar Shailender S. , Dunlay Christopher J. , Simeone Diane M. , Nagrath Sunitha 
Published: May 2015

Abstract
Membrane bound extracellular vesicles, including microvesicles and exosomes, are secreted by both normal and cancerous cells into the extracellular space and in blood circulation. These circulating extracellular vesicles (cirEVs) and exosomes in particular, are recognized as a potential source of disease biomarkers and also carry signature molecules for early stage cancer detection. However, to exploit the use of circulatory exosomes as a new diagnostic tool, a rapid, high-throughput and reproducible method is required for their isolation and to allow their molecular analysis. We have developed a simple and a low cost microfluidic-based platform to analyze cirEVs enriched in exosomes directly from blood serum in a single step allowing simultaneous capture and quantification of exosomes. To capture exosomes with specificity, we employed a microfluidic device “ExoChip” functionalized with antibodies against exosomes to capture cirEVs. Subsequent staining with a fluorescent dye that specifically labels the exosomes, we quantitated exosomes using a standard plate-reader. Ten independent ExoChip experiments performed using serum obtained from five pancreatic cancer patients and five healthy individuals revealed a statistically significant increase (2.34±0.31 fold, p &lt;0.001) in exosomes captured in cancer patients when compared to healthy individuals. Exosomal origin of ExoChip immobilized vesicles were further confirmed using immuno-electron-microscopy and Western blotting. In addition, we demonstrate the ability of ExoChip to recover exosomes with intact RNA enabling profiling of exosomal-microRNAs through openarray analysis, which has potential applications in biomarker discovery. Based on our findings, ExoChip is a well suited platform to be used as an exosome-based diagnostic and research tool for molecular screening of human cancers.
Citation Format: Shailender S. Kanwar, Christopher J. Dunlay, Diane M. Simeone, Sunitha Nagrath. Simultaneous isolation and quantification of circulating exosomes for cancer biomarker discovery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5591. doi:10.1158/1538-7445.AM2014-5591
Abstract 5603: Aryl hydrocarbon receptor, a receptor for environmental pollutants, promotes tumorigenesis via intestine-specific homeobox expression in hepatocellular carcinoma
Authors: Wang Li-Ting , Wang Shen-Nien , Hsu Shih-Hsien 
Published: May 2015

Abstract
Environmental pollutants often cause diseases. Aryl hydrocarbon receptor (AHR), a major transcriptional factor in the xenobiotic response, regulates cellular signaling and metabolism, thereby influencing disease progression. The detailed regulatory mechanisms, however, remain unclear. Here we demonstrate that AHR expression promotes tumorigenesis and is associated with shorter survival time in HCC patients. These phenomena appear to be mediated by activation of a target proto-oncogene, intestine-specific homeobox (ISX), in vitro and in vivo. The strong correlation of expression and cellular transcriptional regulation between AHR and ISX (in tumor and hepatoma cells) underscore the significant role of this duo in HCC tumorigenesis and prognosis. Our experiments with the ablation of ISX expression in AHR-mutant mice and hepatoma cells further support the essential roles of AHR and ISX in liver and tumor development. These results advance the understanding of the cellular function of AHR and of its downstream gene, ISX, in HCC progression. Our data may help to develop a new therapeutic approach to HCC.
Citation Format: Li-Ting Wang, Shen-Nien Wang, Shih-Hsien Hsu. Aryl hydrocarbon receptor, a receptor for environmental pollutants, promotes tumorigenesis via intestine-specific homeobox expression in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5603. doi:10.1158/1538-7445.AM2014-5603
Abstract 561: A natural copy number variant in the GAEC1 oncogene is associated with breast cancer susceptibility
Authors: Gopalan Vinod , Smith Robert A. , Pillai Suja , Griffiths Lyn R. , Lam Alfred K-Y 
Published: May 2015

Abstract
The recently discovered GAEC1 oncogene, located at 7q22, has been found to be amplified in esophageal and colorectal cancers and is associated with altered clinical characteristics in those diseases. Amplification studies in these cancers showed variation in copy number in normal tissues, indicating a potential natural copy number variant (CNV) of GAEC1. In this research, the presence of such a CNV and its association with sporadic breast cancer development was tested in a population of 190 Caucasian women with breast cancer and a population of age, sex and ethnicity matched controls. Data produced by qPCR confirmed the presence of a CNV for GAEC1 in both cancer and control populations, with three common copy number types and several uncommon values, representing up to a 64-fold difference in GAEC1 copies. In addition, Chi-square analysis of copy number types indicated that increased GAEC1 copy number is associated with cancer development. This includes analysis using only the common copy number types (p=0.05) as well as considering all genotypes on a High/Low gene dosage basis (p=0.03). Overall risk for breast cancer was found to be slightly increased in high dose individuals (OR 1.552 (95% CI 1.035-2.338)). These results indicate that GAEC1 may be an important gene in the development of breast cancer, and that examination of its copy number in patient DNA may be a useful addition to genetic risk markers in sporadic cases.
Citation Format: Vinod Gopalan, Robert A. Smith, Suja Pillai, Lyn R. Griffiths, Alfred K-Y Lam. A natural copy number variant in the GAEC1 oncogene is associated with breast cancer susceptibility. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 561. doi:10.1158/1538-7445.AM2014-561
Abstract 575: NKX6.1 functions as a tumor suppressor in hepatocellular carcinoma
Authors: Li Hsin-Jung , Shih Yu-Lueng , Yan Ming-De , Yu Pei-Ning , Lin Ya-Wen 
Published: May 2015

Abstract
In addition to genetic alterations, epigenetic alterations have been increasingly recognized as a key event for carcinogenesis. Methylation of CpG islands in promoter regions is almost associated with transcriptional silencing and is implicated in tumor suppressor gene (TSG) inactivation in cancer cells. Our previous data showed that NKX6.1 promoter is hypermethylated and downregulated in hepatocellular carcinoma (HCC) cell lines. The goal of this study was to elucidate whether NKX6.1 is a tumor suppressor gene in HCC.
All HCC samples with NKX6.1 promoter hypermethylation showed downregulation of NKX6.1 expression using quantitative methylation-specific PCR and quantitative RT-PCR analysis. In addition, the expression of NKX6.1 in HCC cell lines can be restored by treatment with DNA methyltransferase (DNMT) inhibitor, 5-aza-2′-deoxycytidine. These findings indicate that NKX6.1 is frequently silenced in HCC via promoter methylation. We then cloned and determined the putative promoter of NKX6.1 by luciferase reporter assay. The Sp1 site in the NKX6.1 promoter region is important for the promoter activity. When we treated cells with Trichostatin A (TSA), a histone deacetylase inhibitor (HDACi), the NKX6.1 promoter activity increased. These data suggest that promoter methylation and histone modification may take part in the epigenetic silencing of NKX6.1 in HCC. Overexpression of NKX6.1 significantly suppressed transformation in HepG2 and SK-Hep1 cells; however, there is no significant effect on cell viability. Moreover we use a xenograft model to demonstrate the suppressor effects of NKX6.1 on tumor formation in vivo. Taken together, these data suggest that NKX6.1 might be a candidate tumor suppressor in HCC in vitro and in vivo.
Citation Format: Hsin-Jung Li, Yu-Lueng Shih, Ming-De Yan, Pei-Ning Yu, Ya-Wen Lin. NKX6.1 functions as a tumor suppressor in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 575. doi:10.1158/1538-7445.AM2014-575
Abstract 578: RARRES1 is a tumor suppressor in triple-negative breast cancer cell lines
Authors: Coyle Krysta M. , Vaghar-Kashani Ahmad , Wong Florence , Dean Cheryl , Giacomantonio Carman , Marcato Paola 
Published: May 2015

Abstract
Increasing evidence suggests that retinoic acid (RA) signaling is of great importance in the progression and metastasis of different cancer types. We have previously reported that MDA-MB-231 and MDA-MB-468 triple-negative breast cancer cell lines display different responses to increased retinoic acid: retinoic acid increases MDA-MB-231 xenograft growth and decreases growth MDA-MB-468 xenografts. To investigate what may be responsible for these opposite responses to RA, we have investigated the role of retinoic acid receptor responder protein 1 (RARRES1).
RARRES1 is an RA-inducible gene which has not yet been fully characterized. Despite its unknown function, many independent studies have reported the tumor suppressive function of RARRES1 in multiple cancer types. Interestingly, our previous data indicates that high levels of RARRES1 in clinical breast cancer samples is correlated with poorer outcomes for patients. In particular, high expression of RARRES1 is associated with triple-negative breast cancers as well as with more aggressive cancers (by Ki67 positivity, as well as nuclear, mitotic, and overall grade).
Thus, to determine the role of RARRES1 in breast cancers, we have performed in vitro cell proliferation and in vivo xenograft assays. We report that knockdown of RARRES1 in MDA-MB-231 and MDA-MB-468 cells leads to increased cell proliferation in vitro and in in vivo xenografts.
RARRES1 is proposed to regulate a number of genes, including the hypothesized tumor suppressors discs large homolog 2 and protein phosphatase 2A, the proto-oncogene valosin-containing protein (p97), and ankyrin repeat domain-containing protein 26 which is of unknown function. We are investigating the regulation of these genes by RARRES1 in MDA-MB-231 and MDA-MB-468 triple-negative cell lines. We expect that the RARRES1 tumor suppressor is one of many genes induced by RA which form a complex signaling pathway regulating the response of cells to RA.
We conclude that RARRES1 is a tumor suppressor in MDA-MB-231 and MDA-MB-468 triple-negative breast cancer cell lines; however, we continue to investigate the discrepancy between this finding and our previous clinical data.
Citation Format: Krysta M. Coyle, Ahmad Vaghar-Kashani, Florence Wong, Cheryl Dean, Carman Giacomantonio, Paola Marcato. RARRES1 is a tumor suppressor in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 578. doi:10.1158/1538-7445.AM2014-578
Abstract 579: HPP1's tumor suppressive effects are mediated by ectodomain shedding but not by juxtacrine signaling
Authors: Elahi Abul , Ajidahun Abidemi , Clark Whalen , Hernandez Jonathan , Humphries Leigh Ann , Shibata David 
Published: May 2015

Abstract
Introduction: The tumor suppressor gene; HPP1 is downregulated in over 80% of colorectal cancers (CRC) and has potential as a serum and stool-based biomarker. HPP1 is a secreted transmembrane protein that contains an Epidermal Growth Factor (EGF) - like domain, two follistatin modules, and a cytosolic tail with a potential G-protein activating motif. The soluble ectodomain of HPP1 gene may undergo cleavage and functions as an EGF-like ligand which may bind to erbB family receptors. We sought to investigate the importance of cleavage and the possiblity of a juxtacrine role of the flanking EGF-like domain in the context of HPP1's tumor suppressive function..
Methods: An HPP1 double deletion construct (DD) lacking the juxtamembrane stalk cleavage site and an additional 4 amino acid residues (299-320) that constitutes the critical portion of the EGF-like domain was developed by PCR-based overlap extension mutagenesis. HPP1 non-expressing HCT116 cell lines were transfected with either wild-type HPP1 (WT), empty vector (EV) or double deletion construct (DD). Effects on proliferation (MTT assay) and anchorage-indpendent growth (soft agar assay) were evaluated.
Results: We have previously shown that overexpression of HPP1 results in substantial reduction in proliferation, growth in soft agar, and tumorigenicity. We have also identified that transfection of HPP1 with a deleted stalk sequence cleavage site (amino acid residues 303-320) results in a near-complete attenuation of its tumor suppressive effects. In order to determine whether there is a contributory juxtacrine effect of non-cleaved HPP1, we transfected the double deletion construct with a non-functioning EGF-like domain. Successful transfections of EV, WT, and DD were confirmed by RT-PCR. DD cells had similar proliferative potential and growth in soft agar when compared to EV cells (p = 0.609 and p= 0.263, respectively). When compared to WT, DD cells demonstrated a loss of HPP1's growth suppressive impact on cellular proliferation (optical density; 0.16± 0.03 vs. 0.31±0.04, p= 0.0001) and colony formation in soft agar (14.7 ± 5.5 vs. 278 ± 95.0, p= 0.009).
Conclusion: HPP1's tumor suppressive effects in colorectal cancer require cleavage and ectodomain shedding. However, it is unlikely that HPP1's biologic functions are mediated via an additional juxtacrine mechanism in this setting.
Citation Format: Abul Elahi, Abidemi Ajidahun, Whalen Clark, Jonathan Hernandez, Leigh Ann Humphries, David Shibata. HPP1's tumor suppressive effects are mediated by ectodomain shedding but not by juxtacrine signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 579. doi:10.1158/1538-7445.AM2014-579
Abstract 580: Epigenetic silencing of ARRDC3 expression in basal-like breast cancer cells
Authors: Song Young Hwa , Chung Jun 
Published: May 2015

Abstract
Arrestin domain-containing 3 (ARRDC3) is a tumor suppressor whose expression is either lost or suppressed in basal-like breast cancer (BLBC). However, the mechanism by which BLBC suppresses ARRDC3 expression is not established. Here, we show that expression of ARRDC3 in BLBC cells is suppressed at the transcriptional level. Suppression of ARRDC3 expression in BLBC cells involves epigenetic silencing as inhibitors of class III histone deacetylases (HDACs) significantly restores ARRDC3 levels in BLBC cells. SIRT2, among class III HDACs, plays a major role in epigenetic silencing of ARRDC3 in MDA-MB-231 cells. Acetylation levels of the ARRDC3 promoter in BLBC cells is significantly lower than that of other sub-types of BC cells. Chromatin immunopreciptitation analysis established SIRT2 binding at ARRDC3 promoter in BLBC cells. Our studies indicate that SIRT2 dependent epigenetic silencing of ARRDC3 is one of the important events that may contribute to the aggressive nature of BLBC cells.
Citation Format: Young Hwa Song, Jun Chung. Epigenetic silencing of ARRDC3 expression in basal-like breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 580. doi:10.1158/1538-7445.AM2014-580
Abstract 619: Selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer
Authors: Molloy Mary Ellen , White Bethany Perez , Zhao Huiping , Michalsen Bradley T. , Patel Hitisha K. , Zhao Jiong , Xiong Rui , Siklos Marton I. , Thatcher Gregory R.J. , Tonetti Debra A. 
Published: May 2015

Abstract
Endocrine-resistant breast cancer, whether de novo or acquired, is a major clinical obstacle. Although recent clinical trials have demonstrated the efficacy of 17β-estradiol (E2) or diethylstilbestrol (DES) following exhaustive use of antiestrogens, E2 treatment is associated with major side effects such as an increased risk of other gynecological cancers, deterring the clinical community from adopting it as a treatment strategy. Our lab has previously shown that Protein kinase C alpha (PKCα) overexpression predicts tamoxifen (TAM) resistance in the clinic (Tonetti DA et al., Br J Cancer. 2003) and may also predict a positive response to an estrogenic therapy (Chisamore MJ et al., Clinical Cancer Research. 2001). Further, the ectopic overexpression of PKCα in T47D breast cancer cells, led to a TAM-resistant, E2-inhibited phenotype in vivo which was accompanied by the translocation of estrogen receptor alpha (ERα) to extranuclear sites (Perez White B et al., Molecular Cancer. 2013). The purpose of this study was to identify novel selective estrogen mimics (SEMs), which could achieve the positive therapeutic effects of E2 treatment in TAM-resistant breast cancers, while minimizing the side effects. In vitro screening identified two SEMs, BTC and TTC-352, which displayed estrogenic activity in breast cancer cell lines. BTC and TTC-352 treatment resulted in significant tumor regression in two xenograft models of TAM-resistant, PKCα-overexpressing breast cancer. Similar to E2, T47D:A18/PKCα tumor regression was accompanied by translocation of ERα to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment, however, did not result in growth of parental, TAM-sensitive xenograft tumors. Endometrial thickening, caused by both E2 and TAM, is directly associated with gynecological carcinogenesis and uterine cancer. Interestingly, SEM treatment did not increase uterine weight in mice suggesting negligible hormonal stimulation in gynecological tissues. Both BTC and TTC-352 resulted in regression of two TAM-resistant breast cancer models, while displaying enhanced safety compared to E2 and TAM. These data suggest that further development of SEMs targeted to TAM-resistant breast cancer is a feasible therapeutic strategy.
Citation Format: Mary Ellen Molloy, Bethany Perez White, Huiping Zhao, Bradley T. Michalsen, Hitisha K. Patel, Jiong Zhao, Rui Xiong, Marton I. Siklos, Gregory R.J. Thatcher, Debra A. Tonetti. Selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 619. doi:10.1158/1538-7445.AM2014-619