bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1395: Identification of genes and pathways related to lymphovascular invasion in axillary-node negative breast cancer: A bioinformatic analysis of gene expression data
Authors: Blais Mathieu , Pinnaduwage Dushanthi , Bull Sheley , Andrulis Irene L. 
Published: May 2015

Abstract
Breast Cancer patients whose disease has not spread to the lymph nodes (axillary node-negative breast cancer, ANNBC) generally have a good prognosis; however, 20-30% will experience a recurrence. We previously reported that the presence of Lymphovascular invasion (LVI) is an independent predictor of recurrence in ANNBC. Given that breast cancers generally metastasize through LVI, identification of genes with altered expression when comparing LVI+ from LVI- tumors is relevant from both the fundamental and the clinical perspective. To discover genes and pathways involved in LVI and recurrence in ANNBC we performed differential gene expression microarray analysis of LVI+ (n = 37) and LVI- (n=68) ANNBC tumors and assessed pathway enrichment using Ingenuity IPA. We also analysed differences within the LVI+ group designed to compare genes for their association with early recurrence (n = 14; ≤ 4 years) versus free of recurrence for at least 10 years (n = 23). The biofunctions predicted to be activated that distinguish LVI+ from LVI- tumors are largely related to cell movement and invasion. Those enriched in the subset of patients with early recurrence were mostly related to cell fate. In addition, we observed that inflammation related pathways are enriched in the LVI+ subgroup that undergoes early recurrence. TGF-β1 was predicted to be an upstream regulator in the LVI+ vs LVI- dataset and also highly ranked in the early recurrence vs. late recurrence analysis. Our bioinformatics analyses are consistent with a migratory phenotype for cancer cells associated with LVI. The results suggest important pathways as well as upstream regulators associated with LVI and recurrence that are involved in invasion and cell fate biofunctions. The findings are currently being evaluated through validation and functional studies.
Note: This abstract was not presented at the meeting.
Citation Format: Mathieu Blais, Dushanthi Pinnaduwage, Sheley Bull, Irene L. Andrulis. Identification of genes and pathways related to lymphovascular invasion in axillary-node negative breast cancer: A bioinformatic analysis of gene expression data. [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 1395. doi:10.1158/1538-7445.AM2014-1395
Abstract 1396: Musashi 1 stabilizes TAC1 transcript in breast cancer cells to increase the production of onco-substance P
Authors: Nahas George R. , Murthy Raghav G. , Patel Shyam A. , Greco Steven J. , Rameshwar Pranela 
Published: May 2015

Abstract
Despite improved education and aggressive treatments, the mortality of breast cancer (BC) remains high. The TAC1 gene exerts oncogenic effects partly due to its major peptide, substance P, inducing the production of cytokines, which facilitate expression of the tumor-promoting truncated neurokinin-1 receptor. In turn, TAC1 facilitates metastasis to bone marrow and brain. TAC1 expression in BC cells (BCCs) occurs partly through increased translation of its mRNA. Cytosolic extracts from TAC1-expressing cells (BCCs and ectopic expression in non-tumorigenic breast cells) were analyzed for the candidate RNA-binding protein. In vitro translational, RNA stabilization, RNA shift and proteomic analyses identified a 40 kDa binding protein, which interacted with Exon 7 of the 3′ UTR of TAC1. Western blots and RNA supershift assay identified musashi 1 (Msi1) as the TAC1 mRNA binding protein. The data also indicated that TAC1 expression was sufficient for an increase in Msi1. A reporter gene system utilizing the TAC1 3′ UTR indicated that Msi1 competed with the endogenous translational suppressors, miR-130a and -206 for the same interacting site. Use of anti-miRs, Msi1 shRNA and the reporter gene system confirmed Msi1 as the stabilizer of TAC1 mRNA to increase the production of substance P. In vivo studies with nude mice showed reduced tumor growth with Msi1 knockdown BCCs compared to control. Msi1 knockdown retracted the tumor, indicating a role in tumor initiation. These findings correlated with a loss of two stem cell genes, REST and Oct4. In summary, this study identified Msi1 as a central RNA binding protein, which enhanced expression of the oncogenic TAC1 in BCCs. The data also suggested that Msi1, through TAC1 might be important in tumor initiation. These findings have clinical implications as a new drug target to reverse the oncogenic effects of TAC1. Furthermore, the feasibility of targeting TAC1 is evident since its receptor antagonist such as aprepitant are already approved by the FDA.
Citation Format: George R. Nahas, Raghav G. Murthy, Shyam A. Patel, Steven J. Greco, Pranela Rameshwar. Musashi 1 stabilizes TAC1 transcript in breast cancer cells to increase the production of onco-substance P. [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 1396. doi:10.1158/1538-7445.AM2014-1396
Abstract 1397: Simultaneous down-regulation of WWOX and DOK1 genes in non-small cell lung cancer (NSCLC) patients
Authors: Baykara Onur , Ekizoglu Seda , Tuna Esin , Demirkaya Ahmet , Kaynak Kamil , Kose Hikmet , Buyru Nur 
Published: May 2015

Abstract
Lung cancer is the main cause of cancer-related death worldwide and genetic, epigenetic and environmental factors affect the outcome of the disease. The WW domain-containing oxidoreductase (WWOX) gene is a putative tumor suppressor gene located on chromosome 16q23.3-24.1. It is composed of 9 exons and codes for a 414 amino acid protein. The WWOX gene has been previously reported to lose its tumor suppressor effect in several types of cancer including lung, ovarian, breast, stomach, uroepithelial and nasopharyngeal carcinomas. Docking Protein 1 (DOK1) is another putative tumor suppressor gene located on chromosome 2p13 and is known to be down-regulated and hypermethylated in various types of cancer including lung, breast or head and neck cancers and Burkitt lymphoma. WWOX activates MEK2 (MAP2K2-mitogen activated protein kinase kinase 2) which plays a crucial role in mitogen growth factor signal transduction. This activation increases ERK signaling in the MAPK/ERK pathway leading to transcription. The WWOX protein has two WW (tryptophan) domains which recognize the proline-rich region of other proteins. The DOK1 protein has a proline-rich region on its COOH terminal which may interact with the WWOX protein. DOK1 activates the RAS-GAP (GTPase activating proteins) signaling pathway leading to transcription when it is phosphorylated. Both WWOX and DOK1 also play important roles in the wnt/beta-catenin signaling pathway. The aim of this study was to investigate the relationship between WWOX and DOK genes by analyzing the expression levels of WWOX and DOK1 using RT-PCR in tumor tissue samples obtained from patients with non small cell lung cancer (NSCLC). When we analyzed expression levels by Spearman's Rank Correlation Coefficient Test, we observed down-regulation of the WWOX and DOK1 expression by 92.3% and 69.4% of the patients, respectively. Expression levels of WWOX and DOK both decreased simultaneously in 66.7% of the patients. We found a significant positive correlation between the expression levels of the WWOX and DOK1 genes when analyzed using the Wilcoxon Signed Ranks Test (p=0.033).
Citation Format: Onur Baykara, Seda Ekizoglu, Esin Tuna, Ahmet Demirkaya, Kamil Kaynak, Hikmet Kose, Nur Buyru. Simultaneous down-regulation of WWOX and DOK1 genes in non-small cell lung cancer (NSCLC) patients. [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 1397. doi:10.1158/1538-7445.AM2014-1397
Abstract 1398: Targeting novel co-activators of androgen receptor in castration resistant prostate cancer
Authors: Malik Rohit , Khan Amjad P. , Prensner John R. , Iyer Matthew K. , Borkin Dmitry , Wang Xiaoju , Jiang Xia , Subramaniam Shruthi , Shi Yang , Stender Rachell , Wu Yi-Mi , Cao Xuhong , Grembecka Jolanta , Cierpicki Tomasz , Chinnaiyan Arul 
Published: May 2015

Abstract
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castrate resistant prostate cancer (CRPC), an advanced and frequently lethal form of this disease. Substantial prior work has focused on targeting AR directly; however, the identification and therapeutic targeting of co-activators of AR signaling remains an underexplored area of potential clinical significance. Here we demonstrate that the MLL complex acts as a co-activator of AR signaling. AR directly interacts with the sub-unit menin to recruit MLL and its complex to AR target genes. Inhibition of the menin-MLL interaction can block AR signaling and inhibit the formation of castration resistant tumors in vivo. Furthermore, we find that menin is up-regulated in localized and metastatic prostate cancer and high menin expression correlates with poor overall survival. Taken together our study identifies a novel co-activator complex of AR that can be targeted in CRPCs.
Citation Format: Rohit Malik, Amjad P. Khan, John R. Prensner, Matthew K. Iyer, Dmitry Borkin, Xiaoju Wang, Xia Jiang, Shruthi Subramaniam, Yang Shi, Rachell Stender, Yi-Mi Wu, Xuhong Cao, Jolanta Grembecka, Tomasz Cierpicki, Arul Chinnaiyan. Targeting novel co-activators of androgen receptor in castration resistant prostate 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 1398. doi:10.1158/1538-7445.AM2014-1398
Abstract 1399: NRF2 mutations are frequent in early rat preneoplastic hepatic lesions and in human hepatocellular carcinomas positive for the stem/progenitor cell marker KRT-19
Authors: Zavattari Patrizia , Perra Andrea , Kowalik Marta A. , Angioni Maddalena M. , Menegon Silvia , Petrelli Annalisa , Quagliata Luca , Ledda-Columbano Giovanna M. , Terraciano Luigi , Giordano Silvia , Columbano Amedeo 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is a multistage process but the nature of the molecular changes associated to the different steps, particularly the very early steps, is largely unknown. Recently, we have shown that activation of the Keap-1-NRF2 pathway is a very early event in the Resistant-Hepatocyte (R-H) rat model of hepatocarcinogenesis, suggesting that dysregulation of this pathway may have a causal role in HCC development.
The aim of the present study was to investigate by Sanger fluorescence-based sequence analysis whether and when NRF2 mutations could occur in this experimental model. The results showed that mutations of NRF2 are extremely frequent (17/19; 90%) in early preneoplastic lesions positive for the stem/progenitor cell marker KRT-19, which are considered to be the precursor cell population of HCC in this model. Notably, all the mutations were missense and involved the Keap1-NRF2 binding regions. Mutations of Keap-1 were more rare and were found only in preneoplastic lesions lacking NRF2 mutations (10%). KRT-19 positive HCCs arising 1 year later also showed a high percentage of NRF2 mutation (&gt; 50%), suggesting that mutation of this gene provides a selective advantage towards progression to HCC. Finally, preliminary studies in a subset of KRT-19 positive human HCCs, which are known to exhibit the worse prognosis, showed the presence of NRF2 mutations in a very high percentage (55%) of tumors. On the opposite, no mutations were detected in KRT-19 negative human HCCs.
Conclusion: Our results demonstrate that mutations of NRF2 are highly frequent in a subset of human HCCs (KRT-19+) characterized by poor prognosis. Moreover, the findings stemming from the multistage carcinogenic rat model demonstrate that NRF2 mutation is a very early event, suggesting that dysregulation of the NRF2-Keap1 pathway is likely essential for the clonal expansion of KRT-19+ preneoplastic hepatocytes to HCC.
Citation Format: Patrizia Zavattari, Andrea Perra, Marta A. Kowalik, Maddalena M. Angioni, Silvia Menegon, Annalisa Petrelli, Luca Quagliata, Giovanna M. Ledda-Columbano, Luigi Terraciano, Silvia Giordano, Amedeo Columbano. NRF2 mutations are frequent in early rat preneoplastic hepatic lesions and in human hepatocellular carcinomas positive for the stem/progenitor cell marker KRT-19. [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 1399. doi:10.1158/1538-7445.AM2014-1399
Abstract 1401: Transcription of angiogenin and ribonuclease 4 is regulated by RNA polymerase III elements and a CTCF-dependent intragenic chromatin loop
Authors: Sheng Jinghao , Luo Chi , Jiang Yuxiang , Hinds Philip W. , Xu Zhengping , Hu Guo-fu 
Published: May 2015

Abstract
Angiogenin (ANG) and ribonuclease 4 (RNASE4), two members of the secreted and vertebrate-specific ribonuclease superfamily, play important roles in cancers and neurodegenerative diseases. The ANG and RNASE4 genes share the same promoters but their structure and regulation are unknown. We have characterized the promoters, defined the transcription start site, and identified a mechanism of transcription regulation that involves both RNA polymerase III (Pol III) elements and CCCTC-binding factor (CTCF) sites. We found that two Pol III elements within the promoter regulate ANG and RNASE4 expression in a position- and orientation-dependent manner. We also provide evidence for the presence of an intragenic chromatin loop between the two CTCF binding sites located in two introns flanking the ANG coding exon. We found that formation of this intragenic loop preferentially enhances ANG transcription. These results suggest a multilayer transcriptional regulation of ANG and RNASE4 gene locus. These data also add more direct evidence to the notion that Pol III elements are able to directly regulate Pol II gene transcription. Furthermore, our data indicate that a CTCF-dependent chromatin loop is able to differentially regulate transcription of genes that share the same promoters.
Citation Format: Jinghao Sheng, Chi Luo, Yuxiang Jiang, Philip W. Hinds, Zhengping Xu, Guo-fu Hu. Transcription of angiogenin and ribonuclease 4 is regulated by RNA polymerase III elements and a CTCF-dependent intragenic chromatin loop. [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 1401. doi:10.1158/1538-7445.AM2014-1401
Abstract 1403: TRIM16 inhibits cell growth through direct interaction and modulation of TDP43 protein stability in cancer cells
Authors: Kim Patrick Y. , Tan Owen , Trahair Toby , Liu Tao , Marshall Glenn M. , Cheung Belamy B. 
Published: May 2015

Abstract
The tripartite motif (TRIM) family of proteins are involved in a diverse range of cellular processes ranging from innate immunity, oncogenesis as well as tumor suppression. A majority of these reported functions occur through protein-protein interactions. Previously, we have found a strong correlation between loss of TRIM16 expression and disease progression in three human cancers: neuroblastoma, squamous cell carcinoma and melanoma. Moreover, our studies have shown that TRIM16 acts as a tumor suppressor in these cancers through effects on cell cycle and migration. In order to better understand the mechanism of TRIM16 in cancer cell growth inhibition, we have identified a novel binding partner of TRIM16 and investigated the functional outcome of the protein-protein interaction. Using the yeast two-hybrid screening tool, we identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein. TDP43 has been described as a RNA/DNA binding protein with a putative role in HIV transcription and reports also suggest that this protein plays a role in a wide range of neurodegenerative diseases. Through co-immunoprecipitation studies, we have demonstrated that TDP43 directly binds to TRIM16 in human BE(2)-C neuroblastoma and MCF7 breast cancer cells. Enforced over-expression of TRIM16 increased the protein half-life of TDP43. We have also shown that TDP43 expression was required for TRIM16 induced inhibition of neuroblastoma and breast cancer cell growth. Moreover, we have shown that two cell cycle regulatory proteins, E2F1 and pRb, were regulated by TRIM16 and TDP43. Taken together, our studies suggest that the novel mechanism by which TRIM16 inhibits cancer cell growth is through the direct interaction and up-regulation of TDP43 protein expression and with consequent effects on E2F1 and phos-Rb.
Citation Format: Patrick Y. Kim, Owen Tan, Toby Trahair, Tao Liu, Glenn M. Marshall, Belamy B. Cheung. TRIM16 inhibits cell growth through direct interaction and modulation of TDP43 protein stability in 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 1403. doi:10.1158/1538-7445.AM2014-1403
Abstract 1404: An EGFR-Stat3-IL6 pathway contributes to NF1 tumor initiation and maintenance
Authors: Wu Jianqiang , Ratner Nancy 
Published: May 2015

Abstract
Neurofibromas are incurable peripheral nerve tumors characteristic of Neurofibromatosis type 1. Development of effective neurofibroma therapies has been hindered by limited understanding of mechanisms underlying neurofibroma formation and growth. We used unbiased insertional mutagenesis screening to identify genes and signaling pathways that drive neurofibroma initiation and growth, and identified Stat3. Immunohistochemistry confirmed phosphorylated STAT3(P-Y705) in all human and mouse neurofibromas. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) significantly delayed neurofibroma formation, and in vitro analysis identified a role for Stat3 in SCP self-renewal and tumor initiation after xenografting. In vivo gain- and loss-of-function studies identified EGFR as the major upstream regulator of SCP P-Stat3. Downstream of P-Stat3, EGFR+ SCPs secreted IL-6, which activated SCPs and mature neurofibroma Schwann cells. Therefore, Stat3 plays a critical role in early SC lineage cells, promoting neurofibroma initiation. Jak/Stat might also play a role in neurofibroma maintenance, as a pharmacological Jak2/Stat3 inhibitor reduced Schwann cell and neurofibroma growth. The data support Jak/Stat as a novel neurofibroma driver pathway and JAK/STAT inhibition as a potential neurofibroma therapeutic strategy.
Citation Format: Jianqiang Wu, Nancy Ratner. An EGFR-Stat3-IL6 pathway contributes to NF1 tumor initiation and maintenance. [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 1404. doi:10.1158/1538-7445.AM2014-1404
Abstract 1407: The influence of EWS-FLI1 on the Rho/Actin/MRTF circuit in Ewing sarcoma
Authors: Katschnig Anna M. , Schwentner Raphaela , Niedan Stephan , Kauer Maximilian O. , Lawlor Elizabeth R. , Aryee Dave N.T. , Kovar Heinrich 
Published: May 2015

Abstract
Ewing sarcoma (ES) is the second most common bone tumor in children and adolescents. The disease is characterized by the expression of the aberrant transcription factor EWS-FLI1, which is a fusion gene product originating from the chromosomal translocation t(11;22)(q24;q12). Despite good treatment outcomes for patients with localized ES, about 25% of patients already harbor metastatic disease upon presentation and are prevalently faced with poor overall survival. The metastatic cascade is a complex process. Remodeling of the actin cytoskeleton is the first step for a cell in order to acquire a migratory phenotype. The major regulator of the actin cytoskeleton is the Rho family of GTPases, which upon G-protein coupled receptor (GPCR) signaling gets activated and promotes the polymerization of monomeric G-actin into stress fibers. Concurrently G-actin releases the myocardin-related transcription factor family (MRTF) of transcriptional coactivators. MRTFs translocate into the nucleus where they, together with the transcription factor serum response factor (SRF), bind to serum response elements (SRE) in the promoter of genes involved in cell adhesion, migration and motility. However, the ternary complex factor (TCF) family, a class of transcriptional coactivators activated through Ras signaling, can compete with MRTFs for SRF complexing and binds to ets-motifs on SRE. The ets-transcription factor EWS-FLI1 has been shown to substitute for TCFs, potentially interfering with SRF target gene expression. We therefore hypothesize that EWS-FLI1 interferes with GPCR downstream signaling by competition with MRTFs. By gene expression profiling, we show that several putative MRTF target genes are repressed in the presence of EWS-FLI1 in ES cell lines and are strongly induced upon EWS-FLI1 knockdown. Using the MRTFA target gene transgelin (TAGLN) as an example, we show that knockdown of MRTFA can only reduce its serum inducibility in the absence but not in the presence of EWS-FLI1 supporting our hypothesis of EWS-FLI1 perturbing GPCR signaling in ES. With this study we want to elucidate the role of EWS-FLI1 in the regulation of early steps of the metastatic process in ES.
Supported by the Liddy Shriver Sarcoma Initiative.
Citation Format: Anna M. Katschnig, Raphaela Schwentner, Stephan Niedan, Maximilian O. Kauer, Elizabeth R. Lawlor, Dave N.T. Aryee, Heinrich Kovar. The influence of EWS-FLI1 on the Rho/Actin/MRTF circuit in Ewing sarcoma. [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 1407. doi:10.1158/1538-7445.AM2014-1407