bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1078: Rosiglitazone inhibits breast cancer growth and proliferation via cyclin D1 inhibition.
Authors: Oberlick Elaine , Taliaferro-Smith LaTonia D. , Harris Wayne , Knight Brandi B. , Nagalingam Arumugam , Waller Edmund , Sharma Dipali 
Published: February 2011

Abstract
Breast cancer ranks as the most commonly diagnosed and second leading cause of cancer death in North American women. Thiazolidinediones (TZDs) are a class of anti-diabetic drugs primarily used to treat type 2 diabetes mellitus by increasing insulin sensitivity; these compounds are also known to possess anti-tumor effects in several cancer cells including lung and breast cancer. The present study was designed to evaluate the antiproliferative effects of Rosiglitazone on triple negative breast cancer cells. MDA-MB-231 breast cancer cells were treated with Rosiglitazone and compared with negative control (without treatment) for modulation of molecules involved in cell-cycle regulation and apoptosis, including cyclin D1, caspase-3 and −9, Bad, and Bax. Our results show that Rosigliatzone suppresses the proliferation of highly-metastatic human breast cancer MDA-MB-231 cell line by increasing the number of cells in G1 and reducing the number of cells progressing through the S-phase of the cell cycle. Further investigation revealed that the mechanism by which Rosiglitazone arrested cells in the G1-phase was via inhibition of cyclin D1 (a cell cycle regulatory protein that is essential for progression through the G1-phase of the cell cycle and has an central pathogenetic role in breast cancer). Our lab has previously shown an essential role of cyclin D1 upregulation in breast cacner growth and proliferation. Collectively, our results suggest that Rosiglitazone inhibits cancer cell proliferation by modulating expression of cyclin D1 and may provide a novel role for the use of Rosiglitazone as a therapeutic antitumorigenic agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1078.
Abstract 1084: Honokiol induces G1 phase cell cycle arrest in human epidermoid carcinoma A431 cells
Authors: Guillermo Ruth F. , Chilampalli Shivani , Chandrasekhar Gudiseva , Kaushik Radhey S. , Fahmy Hesham , Dwivedi Chandradhar 
Published: February 2011

Abstract
Recent studies from our laboratory have indicated that pre applications of honokiol (one hour before) prevent UVB- induced skin cancer development in female SKH-1 mice.
Honokiol reduced significantly the cell viability of A431, as assessed by MTT (IC50 60 μM) and BrdU incorporation assay.
The aim of this study is to investigate the effects of honokiol on the cell cycle of human epidermoid carcinoma A431 cell line and to investigate the influence of honokiol in the A431 cell cycle regulator proteins expression.
A431 cells were treated at different concentrations with honokiol for specified periods of time (8, 16, 24, 32, 40 and 48 hours). Cells were harvested and fixed in 70% ethanol and stored at −20 °C. The cell cycle phase analysis was performed by using a Beckton Dickinson Facstar flow cytometer and CellQuest software. Cell lysates were prepared from A431 cells treated with honokiol in similar conditions; proteins were analyzed by Western blotting.
Treatment with honokiol at concentration 50 μM and time periods of 24, 32, 40 and 48 hours blocked the A431 cell cycle in G1 phase significantly (P&lt;0.05) and decreased the percentage of cells in the S and G2/M phase.
Honokiol affects the expression of proteins involved in the A431 cell cycle regulation, down-regulating the expression of cyclin A, CDK2, CDK4 and CDK6 proteins and up-regulating the expression of p21 and p27 proteins which are CDKs inhibitors.
These findings indicate that honokiol causes cell cycle arrest at G1 phase and alteres the expression of various proteins involved in the G1 phase of A431 cell cycle.
(Supported by Translational Cancer Center Research Grant, funded as 2010 Research Initiative Center by the State of South Dakota).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1084.
Abstract 1087: The expression and activity of actin-regulating protein cofilin are associated with the cell cycle progression
Authors: Chiang Pei-Hsun , Hung Shih-Chieh , Lee Yi-Jang 
Published: February 2011

Abstract
Cofilin is a member of actin depolymerizing factor (ADF)/cofilin family that can regulates actin dynamics for cancer growth and invasion/metastasis. Several lines of evidence have demonstrated that cofilin is associated with the cell cycle regulation, while the underlying mechanisms remain to be addressed. To better understand the involvement of cofilin in cell cycle progression, we dissected the cofilin expression and activity in different phases of the cell cycle. We synchronized human non-small lung A549 cancer cells in G1, S and G2/M phase by serum starvation, double thymidine blockage and nocodazole treatment, respectively. It was found that the expression of endogenous cofilin was weakest in G1 phase, while it was strongest in S phase and was modest in G2/M phase. This observation was further confirmed by detecting the down-regulation of highly expressed cofilin in S phase-synchronized cells entering mid-late S, G2/M and G1 phase of the cell cycle. Interestingly, it also showed that inactive form of cofilin (ser-3 phosphorylated) weakly expressed in S phase and gradually increased when cells progress through G2/M and G1 phases. These results suggest that cofilin expression and activity are coordinately regulated during the cell cycle progression. It is also consistent with our previous findings that enforced expression of cofilin results in G1 phase arrest but not S and G2/M phases. Moreover, the level of cofilin transcripts was not significantly altered in different phases of cell cycle. On the other hand, pretreatment of the proteasome inhibitor MG132 resulted in increase of cofilin in G1 phase, suggesting that the fluctuation of cofilin during cell cycle progression is associated with the protein stability. In addition, transduction of undegradable Y68F form of mutant cofilin potentially led to increase of the G1 percentage. Taken together, precisely regulation of cofilin expression and activity is important for cell cycle progression. Targeting on cofilin may provide alternative therapeutic strategy for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1087.
Abstract 1100: p53 blocks TGFβ-induced breast cancer metastasis by downregulating angiopoietin-like 4
Authors: Elangovan Selvakumar , Prasad Puttur D. , Ganapathy Vadivel , Thangaraju Muthusamy 
Published: February 2011

Abstract
Transforming growth factor β1 (TGFβ1) is a multifunctional growth factor with a complex dual role in tumorigenesis. During the early stages of tumor formation, TGFβ1 acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis in tumor cells. In advanced stage of cancer, many tumor cells become unresponsive to the growth-inhibitory actions of TGFβ1 and become more motile, more invasive, and resistant to apoptosis. The molecular mechanism responsible for the conversion of TGFβ1-associated tumor suppression into TGFβ1-associated pro-oncogenic and pro-metastatic signaling is not known. Thus, identification of the signaling pathway responsible for this process would have a potential impact in developing novel breast cancer therapy. Recent studies have shown that TGFβ1 induces ANGPTL4 expression, which leads to lung metastasis of breast cancer through disruption of the endothelial barrier. ANGPTL4, also known as fasting-induced adipose factor (FIAF), is a circulating protein; it plays a role in adipogenesis, angiogenesis, carcinogenesis and metastasis. The expression of ANGPTL4 is dramatically induced in human metastatic breast cancer cell line MB231 by TGFβ1. While studying the molecular mechanisms that control the TGFβ1-associated ANGPTL4 induction, we found that p53 functions as a potent negative regulator of TGFβ1 dependent induction of ANGPTL4 expression. In human breast cancer cells, TGFβ1 induces ANGPTL4 expression only in p53-null cell lines like MB453 and MB468, and in cell lines which express non-functional p53 like T47D and MB231. TGFβ1 is unable to induce ANGPTL4 expression in cells expressing the functional p53. To identify the mechanism by which p53 inhibits ANGPTL4 expression, we cloned 2.2 kb human ANGPTL4 promoter fragment into luciferase (pGL3-Luc) and GFP (pU3RII-pEGFP) reporter plasmids, and we used these constructs for reporter assays in p53 inducible (p53-Tet-On) MB453 cell line. The results showed that functional expression of p53 in MB453 cells effectively blocks the ability of TGFβ1 to induce the transcriptional activation of ANGPTL4, and suggest that p53 serves as a molecular dictator to block the tumor-suppressive and pro-metastatic actions of TGFβ in breast tissue. These studies describe the molecular processes involved in the regulation of ANGPTL4 expression in breast cancer, and will be helpful in the design and development of novel therapeutic strategies for the treatment of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1100.
Abstract 1101: Reexpression of hSNF5 regulates the transcriptional activity of the p21 promoter through p53 dependent or independent mechanisms in malignant rhabdoid tumors
Authors: Kuwahara Yasumichi , Charboneau Aubri , Knudsen Erik S. , Wissman Bernard E. 
Published: February 2011

Abstract
Malignant rhabdoid tumor (MRT), a highly aggressive cancer of young children, displays inactivation of the hSNF5 gene in primary tumors and cell lines. We have previously reported that reexpression of hSNF5 in MRT cell lines causes a G1 arrest via p21WAF1/CIP1 (p21) mRNA induction. However, the mechanisms of p21 promoter activation by hSNF5 remain unclear.
Because p21 is a transcriptional target of the p53 tumor suppressor gene, we determined the role of p53 in hSNF5-induced p21 activation. We reexpressed hSNF5 in the A204 and TTC642 MRT cell lines, with or without stable knockdown of p53 expression, using adenoviral vectors expressing either hSNF5 and GFP or GFP. While loss of p53 expression significantly inhibited p21 transcriptional activity induced by hSNF5 in A204 cells at 24 hours, it did not alter its activity by hSNF5 after 24 hours in the TTC642 cells. These results suggested that the up-regulation p21 transcription by hSNF5 operated through p53-dependent and -independent mechanisms in the A204 and TTC642 cell lines, respectively. Next, we used chromatin immunoprecipitation (ChIP) analysis of the p21 promoter to determine where hSNF5 appeared at the p21 promoter and whether its recruitment altered binding of other transcription factors or the chromatin landscape. Our results indicated that reexpressed hSNF5 binds within 1 kb of transcript start site (TSS), with maximal enrichment at the TSS in both cell lines. Furthermore, histone acetyltransferases (HATs), RNA polymerase II (RNAPII), and BRG-1 are assembled with p53 and CDK8 (co-activator of p53 transcriptional program) by reexpression of hSNF5 in A204 cells. In contrast, while p53 and CDK8 occupancy did not change after hSNF5 reexpression in the TTC642 cells, HATs, RNAPII, and BRG-1 levels increased at the p21 promoter. These findings correlated with the results of p53 knock-down experiments. Furthermore, histone H3K36 tri-methylation increased downstream of the TSS in both cell lines. These results suggested hSNF5 regulates the initiation activity of the p21 promoter by either itself or p53 recruitment, resulting in the mRNA elongation. Our findings demonstrate that while induction of p21 transcription by hSNF5 in A204 cells depends on p53, it occurs independently of p53 in TTC642 cells. The lack of dependence upon p53 appears to extend to other MRT cell lines tested in our laboratory. Furthermore, our results suggest that hSNF5 may alter p21 transcriptional initiation by itself or through the recruitment of other uncharacterized transcription factors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1101.
Abstract 1106: CEACAM1 expression dependent on p53 after DNA damage
Authors: Shin jae sik , Jin dong-hoon , Hong seung-woo , Kim jee-eun , Jung da-jung , Kang jae-seung , Hwang young-il , Lee wang-jae 
Published: February 2011

Abstract
The glycoprotein carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1) is a membrane-bound protein found in microvilli of the apical colon cell surface. Recently, It was reported that signal transduction through the cytoplasmic domains appears to be important for the tumor suppressor function of CEACAM1 and also apoptosis induction in early tumor development. However, the mechanisms that control CEACAM1 expression are not clear. In this study, we show that CEACAM1 expression is induced in a p53-dependent manner. More importantly, alternative splicing of CEACAM1 to the long form (CEACAM1-4L) and the short form (CEACAM1-4S) is regulated by p53 in human colon carcinoma cells, Hct116. Treatment with etoposide induced CEACAM1 expression in cells that have p53 function, but not in cells lacking p53 function. In addition, knockdown of endogenous wild-type p53 using RNA interference and p53 overexpression by adenoviral vector were paralleled with CEACAM1 expression in Hct116 cells. These results suggest that induction of CEACAM1 in the context of tumor suppression is regulated in a p53-dependent manner and implicate CEACAM1 as a key determinant of cell fate.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1106.
Abstract 1109: Identification of a novel MDM2 splice transcript that lacks nuclear transport signals but harbors the p53 binding motif in human glioma cells
Authors: Antoun Gamil , Ali-Osman Francis 
Published: February 2011

Abstract
MDM2 a nuclear phosphoprotein binds with E3 ubiquitin ligase activity, binds and targets p53 for proteosomal degradation, hence is a negative regulator of p53. Consequently, over-expression of MDM2 results in the loss of p53 tumor suppressor function even in the absence of inactivating mutations in the p53 gene. To date, more than 40 different alternative spliced MDM2 transcript variants have been reported in both normal and tumor cells, with most of these lacking, in part or in full, the p53 binding domain of MDM2. In this study, we examined the levels of MDM2 gene expression in a panel of glioblastoma (GBM) cell lines and in vivo primary tumor xenografts by quantitative PCR /RT-PCR and examined the full length MDM2 cDNAs for the presence of MDM2 splice transcript variants using the nested PCR technique and a combination of direct sequencing and TA vector sequencing. The results showed a significant heterogeneity in MDM2 expression and in MDM2 splice variants among the tumors. Importantly, we identified a novel splice MDM2 transcript that was consistently associated with low MDM2 transcript levels in the tumors. Sequence analysis of this MDM2 spliced transcript showed it to harbor an internal deletion of three exons, namely 7, 8, and 9, containing the nuclear localization signal (NLS), the nuclear export signal (NES) and a portion of the acidic domain (AD). The p53 binding domain was fully conserved. The deletion caused a shift in the MDM2 open reading frame that created a stop codon (TGA) at codon 316. The spliced MDM2 transcript encoded a truncated MDM2 protein that harbors the functional p53 binding motif capable of interacting with the p53 protein but without the ability to localize to the nucleolus. Overall, our results with the 15 tumors showed no strong correlation between the presence of this novel splice MDM2 transcript and the expression levels of p53in the tumors. Studies are ongoing to determine the functional consequences of this novel MDM2 spliced variant on p53 downstream function in glioma cells.
Supported by grants RO1CA112519, RO1CA127872, RO1CA91438, P30CA114236 and P5OCA108786 from the National Institutes of Health (USA).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1109.
Abstract 1114: Linker region of the BRCA2 protein increases chemoresistance to cisplatin: Screen for the characterization of cancer-associated variants
Authors: Warren Curtis R. , Farach-Carson Mary C. , Catts Zohra Ali-Khan 
Published: February 2011

Abstract
Screening for mutations in the BRCA1 and BRCA2 genes is standard for patients with family histories suggesting Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Often, patients present with a familial cancer pedigree and a BRCA sequence containing an uncharacterized missense mutation. Such mutations are termed “Variants of Unknown Significance” (VUS) because their ability to alter function of the protein in vivo is unknown [1]. VUS complicate the genetic counseling process as the genetic counselor cannot advise patients if their VUS predisposes them to cancer. We discovered a novel VUS that occurred in the BRCA2 gene in a cancer registry patient in Delaware. Further mining of this registry identified two novel VUS occurring in the same region of the BRCA2 gene encoding the linker region of the BRCA2 protein, a poorly understood functional region of the protein. The two variants were R2341C and N2452D, both carried by breast cancer patients whose family histories were indicative of HBOC. The Breast Cancer Information Core (BIC)[2] in the National Institutes of Health National Human Genome Research Institute catalogues cancer-associated mutations in BRCA1 and BRCA2, including over 500 mutations reported to occur in the linker region; over 300 of these are VUS's. Our lab-based study focused on the linker region peptide encoded by exons twelve through fourteen of the BRCA2 gene. To develop a new method to characterize VUS in the BRCA2 gene, we chose 13 VUS occurring on evolutionarily conserved residues with varying frequencies. One, I2285V, was reported 79 times, whereas several others were reported only once. To determine if these VUS represent polymorphisms or if they change the function of the BRCA2 protein, we constructed expression plasmids encoding each mutant peptide for use in stable transfection experiments in T47D cells. Four mutant peptide expression clones and a wild-type linker region expression clone were studied by challenging the cell lines with the DNA crosslinking compound cisplatin. Several of the mutants increased survival in transected cell lines, indicating that the linker region peptide may interact directly or indirectly with a protein or DNA partner in the DNA damage repair pathway. In this case, the reported VUS mutations may change the activity of the BRCA2 linker region. We conclude that this may be a good method for screening the effect of VUS on protein function. Further study is required to create a high-throughput, standardized assay for characterization of VUS which would benefit patient and clinician alike.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1114.
Abstract 1116: Epigenetic control of the BRCA1 expression by a metabolic switch
Authors: Di Lijun , Fernandez Alfonso , Gardner Kevin 
Published: February 2011

Abstract
Though deletion or loss of BRCA1 function is the major cause of most familial forms of breast cancer, decreased expression of non-mutated BRCA1 alleles is often found in sporadic breast cancer, suggesting that alterations in BRCA1 transcriptional regulation may contribute to non-inherited forms of breast cancer. In this study, we show that BRCA1 expression is controlled by a tightly regulated dynamic balance between the association of transcriptional co-activators and co-repressors that regulate histone acetylation and chromatin accessibility at the BRCA1 bi-directional promoter to enforce unidirectional transcriptional activation in response to estrogen stimulation. A central regulatory step in the control of the BRCA1 promoter is the eviction of the co-repressor and metabolic sensor C-terminal-binding protein1 (CtBP1). Loss of CtBP1 from the BRCA1 promoter induced by estrogen, CtBP1 RNAi depletion or increasing NAD+/NADH ratio results in elevated histone acetylation, HDAC1 dismissal from the BRCA1 promoter and increased BRCA1 transcription. Notably this level of regulation is lost in the absence of physiological chromatin structure at the BRCA1 promoter. These findings indicate that BRCA1 expression is controlled by a metabolic switch that dynamically influences the localized deposition of epigenetic marks and chromatin structure at the BRCA1 promoter and suggests that caloric intake may influence the levels of tumor suppressor function in mammary tissues.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1116.