bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4641: Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the Cheliensisin A (Chel A) inhibition of cell transformation
Authors: Huang Chuanshu , Zhu Junlan , Li Jingxia 
Published: August 2015

Abstract
Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the present study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP down-regulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A.
Citation Format: Chuanshu Huang, Junlan Zhu, Jingxia Li. Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the Cheliensisin A (Chel A) inhibition of cell transformation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4641. doi:10.1158/1538-7445.AM2015-4641
Abstract 4647: Bioactive tanshinones and tea polyphenols inhibit prostate cancer stem cells by targeting bmi1
Authors: Zhou Jin-Rong , Gong Yi , Abdolmaleky Hamid 
Published: August 2015

Abstract
Prostate cancer (CaP) is the most common invasive malignancy and the second leading cause of cancer-related death in U.S. men. Androgen-independent/hormone-refractory CaP remains the primary cause of CaP death. The search for effective therapeutic and preventive strategies, particularly the ways to intervene in the progression of androgen-independent tumors remains the top priority of CaP research. Prostate cancer stem cells (CSCs) are suggested to be responsible for initiation, progression, drug resistance, recurrence and metastasis of CaP. Strategies that target prostate CSCs may significantly prevent and/or delay cancer progression and metastasis. The objective of this study was to identify the potent natural bioactive compounds for targeting prostate CSCs. The sphere-forming efficiencies in LNCaP, DUCaP, PC3 and DU145 prostate cancer cell lines were 2.8%, 15.7%, 1%, and 5.6%, respectively. The expression of several CSC related biomarkers, such as c-met, c-kit, bmi1 and CD44 were increased, whereas the expression of androgen receptor was decreased in prostate spheres. Natural compounds, especially tanshinones (tanshinone I (T1), tanshinone IIA (T2A), cryptotanshinone) and tea compounds (epigallocatechin gallate (EGCG) and theaflavines), inhibited the sphere-forming efficiency of CaP cells with T1 and T2A the most potent. Furthermore, T1 and EGCG significantly downregulated Bmi1 gene expression and protein level. Since Bmi1 has been reported to be a crucial regulator of stem cell self-renewal and malignant transformation, we further studied the functional role of bmi1 in self-renewal of prostate CSCs. Silencing of bmi1 dramatically inhibited the growth and decreased the sphere-forming ability of CaP cells. Animal studies showed that T1 and EGCG inhibited the growth and metastasis of prostate tumors associated with downregulation of bmi1 expression. The results derived from our preliminary studies suggest that bmi1 may play an important role in self-renewal ability of prostate CSCs, and that some natural bioactive agents, such as T1 and EGCG, may inhibit self-renewal of prostate CSCs in part via downregulation of bmi1 gene expression and function. Supported in part by NCI/NIH R21 CA153355.
Note: This abstract was not presented at the meeting.
Citation Format: Jin-Rong Zhou, Yi Gong, Hamid Abdolmaleky. Bioactive tanshinones and tea polyphenols inhibit prostate cancer stem cells by targeting bmi1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4647. doi:10.1158/1538-7445.AM2015-4647
Abstract 4662: Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment
Authors: Walsh Naomi , Alberts David S. , Brown Powel , Limburg Paul , Sherman Mark , Szabo Eva 
Published: August 2015

Abstract
Background Although a number of cancer chemopreventive agents have now been evaluated in phase II and phase III clinical trials that assess their efficacy and tolerability in both high risk and general populations, few have shown clear efficacy and uptake of approved agents has been disappointingly low. Therefore, chemopreventive agents should undergo rigorous screening prior to clinical trial evaluation in order to improve the selection of suitable agents for testing in large, expensive multi-center phase III trials. The aim of this study is to develop a descriptive method for prioritizing candidate agents for further development.
Methods This framework was developed through a systematic literature review of Pubmed/Medline, Embase and The Cochrane Library. A semi-quantitative assessment focusing on efficacy and toxicity/tolerability was established based on expert input. Data from clinical trials, cancer epidemiological, observational and preclinical studies, including in vivo and in vitro basic research, was used to retrospectively evaluate the clinical application and effectiveness of cancer chemopreventive agents. Two chemopreventive agents with either a positive (aromatase inhibitors (AIs) for breast cancer) or negative (selenium for lung cancer) phase III clinical trial outcome were subsequently evaluated to determine the usefulness of the framework.
Results Chemopreventive agents must reduce or reverse the process of carcinogenesis in normal or pre-malignant tissue with minimal toxicity. Evaluation of efficacy included data from preclinical and animal models, epidemiological studies, and clinical trials (both early phase trials in the organ of interest as well as secondary endpoints from other relevant studies). Agent suitability evaluation included assessment of toxicities, tolerability, and agent specific attributes (PK/PD, bioavailability, dosing, etc.). Examination of selenium and AI historical data in these categories revealed strong concordance with phase III outcomes. The detailed descriptive evaluation of the agents will be presented.
Conclusion This framework provides a descriptive paradigm for cancer chemopreventive agent evaluation through systematic and rigorous interrogation. Thorough, standardized evaluation of all available preclinical, epidemiological, and clinical data should be strongly encouraged to better inform the investments required for clinical trials.
Citation Format: Naomi Walsh, David S. Alberts, Powel Brown, Paul Limburg, Mark Sherman, Eva Szabo. Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2015-4662
Abstract 4714: Targeting p53 mutant cancers through inhibition of the phosphatidylinositol-5-phosphate 4-kinases
Authors: Emerling Brooke M. , Yang Zhiwei , Loughran Ryan , Yang T.Jonathan , Johnson Jared , Pragani Rajan , Davis Mindy , Shen Min , Boxer Matthew , Simeonov Anton , Cantley Lewis C. 
Published: August 2015

Abstract
The bulk of cellular phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) is generated by the canonical pathway in which a 5-kinase converts phosphatidylinositol-4-phosphate (PI-4-P) to PI-4,5-P2. However, several years ago we discovered that PI-4, 5-P2 can also be generated at intracellular sites by a family of kinases that phosphorylate the 4 position of phosphatidylinositol-5-phosphate (PI-5-P), a lipid that was not previously known to exist in nature. These enzymes are called the type 2 phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks). To date, we have shown that a subset of breast cancers express high levels of PI5P4Kα and/or β, and have provided evidence that these kinases are essential for growth in the absence of p53 (Emerling et al., 2013). Furthermore, we showed that PI5P4Kα and β play critical roles in mediating changes in metabolism in response to cellular stress, in particular, stress that occurs in the absence of p53. Here, we disclose the discovery of potent and selective inhibitors of PI5P4K (Kis in the range of 10 to 200 nM). These novel PI5P4K inhibitors have provided us with powerful tools to further investigate the role of the PI5P4K enzymes in cancer metabolism. Through pharmacological inhibition of PI5P4K, we now have support that PI5P4K provides an alternative pathway to p53 in regard to mediating responses to metabolic and oxidative stress, thereby suggesting that the PI5P4K enzymes are essential for survival mechanisms when p53 function is lost. Above all, these inhibitors may be effective therapies not only for breast cancers with genetic aberrations in TP53, but in all cancer types with loss of p53 function.
Supported by DOD Breast Research Program Breakthrough Award to B.M.E.
References
Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Wulf G, Bell EL, Shim H, Choo-Wing R, Bellinger G, Lamia KA, Rameh LE, Sasaki A, Asara JM, Yuan X, Bullock A, Brown V, Signoretti S, and Cantley LC. (2013) Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53 Null Tumors. Cell. Nov 7; 155 (4): 844-57.
Citation Format: Brooke M. Emerling, Zhiwei Yang, Ryan Loughran, T.Jonathan Yang, Jared Johnson, Rajan Pragani, Mindy Davis, Min Shen, Matthew Boxer, Anton Simeonov, Lewis C. Cantley. Targeting p53 mutant cancers through inhibition of the phosphatidylinositol-5-phosphate 4-kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2015-4714
Abstract 476: Loss of chd5-mediated tumor suppression accelerates MYCN-driven neuroblastoma tumorigenesis in zebrafish
Authors: Zimmerman Mark W. , He Shuning , Shin Jimann , Zhu Shizhen , Mansour Marc , Joung Keith , Quan Jinhua , Yusufzai Timur , Look A. Thomas 
Published: August 2015

Abstract
Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system (PSNS) that originates from cells of the primitive neural crest. For the 40% of patients with high-risk disease, current therapies are often ineffective and long-term survival remains obstinately low. A major risk factor in neuroblastoma is hemizygous loss of the 1p36 chromosomal region, which has long been suspected to harbor one or more powerful tumor suppressor genes. Our studies indicate that loss of Chromodomain helicase DNA-binding protein 5 (chd5), which is in this deleted region, cooperates with MYCN overexpression to accelerate in vivo neuroblastoma tumorigenesis. Zebrafish chd5-null alleles were created utilizing both zinc-finger nuclease and TALEN technology. The resulting chd5 mutant fish exhibit abnormal development of the PSNS in the form of expansion of the superior cervical ganglia and enlargement of the interrenal gland (adrenal medulla). In order to examine the effect of chd5 haploinsuficiency on in vivo neuroblastoma tumorigenesis, chd5 mutant fish were crossed with the dbh:MYCN transgenic model resulting in neuroblastoma tumors. Consistent with a tumor suppressor function, chd5 haploinsufficient fish exhibit an accelerated neuroblastoma phenotype with tumors present beginning as early as 6 weeks compared to 15 weeks observed in wildtype fish. The chd5 protein can serve as one of two enzymatic components of the nucleosome remodeling and histone deacetylase (NuRD) complex, which is a repressor of gene expression and is reported to have diverse roles in regulating chromatin organization, developmental signaling and gene stability. Future studies will examine the mechanism and function of chd5 so that the pathways mediating tumor suppression can be elucidated and that essential proteins in these pathways can be targeted in ways that exploit the synthetic lethal relationships that are established.
Citation Format: Mark W. Zimmerman, Shuning He, Jimann Shin, Shizhen Zhu, Marc Mansour, Keith Joung, Jinhua Quan, Timur Yusufzai, A. Thomas Look. Loss of chd5-mediated tumor suppression accelerates MYCN-driven neuroblastoma tumorigenesis in zebrafish. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 476. doi:10.1158/1538-7445.AM2015-476
Abstract 4765: A drill-down approach to identifying an ER negative-specific gene signature
Authors: Worsham Maria J. , Chitale Dhananjay , Chen Kang Mei , Datta Indrani , Stephen Josena K. , Divine George 
Published: August 2015

Abstract
There has been relatively little advancement in changing the management of women with ER negative (ER-) breast cancer (BC). Our objective is to examine the contribution of aberrantly methylated genes to the pathogenesis of ER- BC, determine their utility in refining classification of ER- subtypes [basal-like (BL) and Her2-enriched], in differentiating ER- BC in African American (AA) and Caucasian American (CA) women, and as new prognostic and therapeutic targets for better management of ER- BC.
The methylation status of 40 ER- and 40 ER positive (ER+) breast cancer samples was assessed using the Illumina 450K. A 3-tiered approach was used to call out genes most differentially methylated between ER- and ER+. The top 70 genes were further downsized using the TaqMan low-density array expression assays, Ingenuity Pathway Analysis (IPA) to assess their biologic significance, followed by targeted sequencing (Illumina Miseq). Further assessment of the genes in the 450K TCGA data sets (UCSC Brower 2015) was used for final downsizing.
Of the 70 highly ranked differentially methylated genes, 56 were hypermethylated and 14 hypomethylated, with positive correlation with gene expression for the majority of genes. Expression verification and significant rankings in canonical pathways and bionetworks resulted in further downsizing to 41 genes upon confirmation by targeted sequencing. Further filtering of the 41 genes with 450K TCGA data sets provided additional refinement to a 10 gene candidate panel currently being vetted in a retrospective cohort of over 1000 ER negative BC (with 40% AA).
Our iterative approach to identify an ER negative-specific gene signature has the potential to offer predictive and prognostic markers of improved classification for ER- BC in AA and CA women. Confirmation and validation of these methylation profiles in independent cohorts of BL BC defined by cDNA microarrays should further stratify poor prognosis breast cancers subgroups and serve as targets for epigenetic-modifying agents individualized to AA and CA women with ER- BC. Human therapeutic intervention trials to reverse deleterious epigenetic changes have shown promise in halting tumor growth by reactivation of the tumor suppressor genes or by reversing DNA hypomethylation.
Support: Komen Foundation: KG110218
Citation Format: Maria J. Worsham, Dhananjay Chitale, Kang Mei Chen, Indrani Datta, Josena K. Stephen, George Divine. A drill-down approach to identifying an ER negative-specific gene signature. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4765. doi:10.1158/1538-7445.AM2015-4765
Abstract 4771: Epigenetic modification of LY6K in CGI shore and CGI regulates LY6K gene activation and metastatic function in breast cancer
Authors: Kong Hyun Kyung , Park Sae Jeong , Kim Ye Sol , Park Jong Hoon 
Published: August 2015

Abstract
LY6K is associated with development of the immune response and carcinogenesis. Elevated LY6K by AP-1 activation induces invasion and metastasis by activating the ERK signaling pathway. However, the exact epigenetic mechanism of LY6K gene expression has not been clarified. The CpG island and 5′CGI shore in the region around the transcription start site of the LY6K were predicted using the UCSC genome browser and Methprimer software to elucidate the epigenetic mechanism of LY6K gene regulation and expression. We performed the methylation-specific PCR, bisulfite pyro-sequencing, and bisulfite sequencing to investigate the DNA methylation status of CpG sites from −400 to +500 on the LY6K CpG island and 5′CGI shore. ChIP and ChIP-MSP analysis were performed to confirm the histone modification and DNA methylation status. To validate the inverse correlation between LY6K 5′CGI shore methylation and LY6K expression in vivo, we performed bisulfite pyro-sequencing and tissue microarray using breast carcinoma samples. LY6K expression was inversely correlated with methylation status of CGI and 5′CGI shore in the LY6K of human breast cancer. Moreover, DNA methylation status of LY6K was correlated with histone modification. Treatment of 5-Aza-dC with low LY6K expression caused elevated LY6K expression leading to wound healing. An understanding of epigenetic changes in LY6K may contribute to diagnosing carcinogenic risk and to predict the outcome of patients with breast cancer.
Citation Format: Hyun Kyung Kong, Sae Jeong Park, Ye Sol Kim, Jong Hoon Park. Epigenetic modification of LY6K in CGI shore and CGI regulates LY6K gene activation and metastatic function in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4771. doi:10.1158/1538-7445.AM2015-4771
Abstract 4785: Deficiency of cystathionine beta synthase gene does not affect tumor formation and survival of Eμ-myc mice
Authors: Gupta Sapna , Kruger Warren D. 
Published: August 2015

Abstract
Aberrant DNA methylation is a hallmark of many types of cancers. S-adenosylhomocysteine (AdoHcy) is a strong inhibitor of DNA methytransferases. Deficiency of cystathionine beta synthase gene (Cbs) causes elevation of AdoHcy in variety of tissues. Here we have generated an Eμ-myc mouse model which is either wild type, heterozygous or homozygous for a deletion allele of Cbs (Eμ myc+ Cbs+/+; Eμ myc+ Cbs+/−; Eμ myc+ Cbs−/−). Homozygous Cbs deficient mice in both Eμ myc+ and Eμ myc− background were born at Mendelian frequency indicating that there is no synthetic lethality between Cbs and Eμ myc. In aging, we observed no significant difference in survival of Eμ myc+ Cbs+/+, Eμ myc+ Cbs+/− and Eμ myc+ Cbs−/− mice (Median survival of 150, 149 and 117 days respectively). However, preliminary data shows that tumor tissue from Eμ myc+ Cbs−/− animals has greatly elevated levels of AdoHcy compared to other genotypes. Our studies suggest that elevated levels of AdoHcy has no effect on tumor formation in Eμ myc mice.
Citation Format: Sapna Gupta, Warren D. Kruger. Deficiency of cystathionine beta synthase gene does not affect tumor formation and survival of Eμ-myc mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4785. doi:10.1158/1538-7445.AM2015-4785
Abstract 4822: Lack of expression of FOXO3 correlates with poor prognosis on uterine sarcomas
Authors: Almeida Thais G. , Garcia Natalia , Cunha Isabela W. , Baiocchi Glauco , Soares Fernando A. , Maciel Gustavo A. , Baracat Edmund C. , Carvalho Katia C. 
Published: August 2015

Abstract
Background: Uterine sarcomas are rare mesodermic tumors that represent approximately 3% of all uterine cancers. They display histological diversity and aggressive behavior, with early dissemination and high mortality when compared with epithelial tumors. Due to their diversity and rarity, there is no consensus related to risk factors for poor prognostic and appropriated treatment. The knowledge of the gene expression regulation can contribute to a better understanding of these neoplasms. Recently it was demonstrated an essential role for the forkhead transcription factor FOXO3 in the regulation of diverse cellular functions and tumors development. Our aim was to study the expression profile of the transcription factor FOXO3 in several histological types of uterine sarcoma. Method: we evaluated 100 samples of uterine sarcomas (including leiomyosarcomas, carcinosarcomas, adenosarcomas and endometrial stromal sarcomas), leiomyomas and myometrium obtained from patients during the period of 2000 to 2012. FOXO3 protein expression was assessed by immunohistochemistry. mRNA expression was evaluated by quantitative Real Time PCR. The results were submitted to statistical analyses together with patient's data. Results: We observed that carcinosarcomas (CSS) and adenosarcomas (ADS) showed the highest FOXO3 protein signal, considering exclusively the mesenchymal component. Concerning to muscular tumors (leiomyoma and leiomyosarcoma), we found an increasing enhancement of this protein expression from the myometrium to myoma and leiomiosarcoma, both in protein and transcriptional levels. Statistical analysis showed that tumors with weak or lack of FOXO3 protein present poor prognosis, regardless of their histological type. Conclusion: FOXO3 protein expression seems to be a relevant role in uterine sarcomas, however further analyses are needed.
Citation Format: Thais G. Almeida, Natalia Garcia, Isabela W. Cunha, Glauco Baiocchi, Fernando A. Soares, Gustavo A. Maciel, Edmund C. Baracat, Katia C. Carvalho. Lack of expression of FOXO3 correlates with poor prognosis on uterine sarcomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4822. doi:10.1158/1538-7445.AM2015-4822