bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1454: Estrogen receptor signaling in FTE of BRCA mutation carriers
Authors: Dodds Leah V. , Nelson Omar L. , Sowamber Ramlogan , Rodrigues Andres , Castro Victoria de , Henry Wendell , Morales Guillermo , Slomovitz Brian , Shaw Patricia , George Sophia H. 
Published: July 2017

Abstract
Genetic and reproductive factors predicate epidemiological risk factors underlying epithelial ovarian cancer. The fallopian tube epithelia (FTE), the presumptive etiological site of high-grade serous ovarian cancer (HGSC), is a hormonal responsive tissue. Estrogen is known to promote cell proliferation and its metabolism produces reactive oxygen species that damage DNA and promote tumorigenesis. Estrogen receptor (ER) is rarely mutated, amplified or deleted in HGSC, yet only 10% of patients respond to anti-estrogen treatment, suggesting that intrinsic variables to the ER pathway contribute to this clinical outcome. TP53 mutations occur in almost 100% of HGSCs, indicating that mutated p53 supports a model as an early event in the pathogenesis of HGSC. We hypothesized that in the presence of dysfunctional p53, subsequent promiscuous binding of ER will yield aberrant signaling, ultimately significantly contributing to cellular transformation. Mutant p53 and ER co-localize in FTE cells, suggesting potential synergy. We established cell lines with p53 mutations and treated them with estradiol, an estrogen analog, to observe any changes in response. The genome binding sites of ER-regulated transcription factors were then identified and mapped by whole genome chromatin immunoprecipitation-deep sequencing (ChIP-Seq). The data generated will facilitate the development of gene signatures that will predict response to anti-estrogen therapy in serous ovarian cancer patients, and contribute to the discovery of biomarkers to more accurately identify patients who will benefit from hormonal therapies.
Citation Format: Leah V. Dodds, Omar L. Nelson, Ramlogan Sowamber, Andres Rodrigues, Victoria de Castro, Wendell Henry, Guillermo Morales, Brian Slomovitz, Patricia Shaw, Sophia H. George. Estrogen receptor signaling in FTE of BRCA mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1454. doi:10.1158/1538-7445.AM2017-1454
Abstract 147: Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation
Authors: Shi Peiguo , Zhou Zhongmei , Liu Rong , Chen Ceshi 
Published: July 2017

Abstract
Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. A stem cell transcription factor KLF5 is over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Previously, we demonstrated that Mifepristone suppresses basal TNBC stem cells by down-regulating KLF5 expression through inducing the expression of miR-153. In this study, Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. We demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of KLF5 and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced GSK3β-mediated KLF5 protein phosphorylation and degradation through the inhibition of PKA activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB and KLF5 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway.
Citation Format: Peiguo Shi, Zhongmei Zhou, Rong Liu, Ceshi Chen. Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 147. doi:10.1158/1538-7445.AM2017-147
Abstract 1474: Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism
Authors: Daibiao Xiao , Dong Junli , Zhao Zihan , Ren Ping , Li Cong , Hu Yufeng , Shi Jianguo , Su Hexiu , Wang Zhaojing , Liu Hudan , Li Bo , Gao Peng , Qing Guoliang 
Published: July 2017

Abstract
Cancer cells amplify the expression of ASC amino acid transporter 2 (ASCT2, also called SLC1A5), a high-affinity glutamine carrier protein, to coordinate metabolic reprogramming and malignant transformation. Yet genetic and/or epigenetic mechanisms underlying the control of ASCT2-mediated glutamine metabolism remain to be clarified. Combined in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor miR-137 as an essential regulator that targets ASCT2 mRNA and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and its decreased transcription, which conversely enhances ASCT2 expression and glutamine metabolism. As such, expression between miR-137 and ASCT2 is inversely correlated in multiple human cancer types, including colorectal carcinomas, glioblastomas, prostate and pancreatic cancers. These findings thus elucidate a universal mechanism responsible for ASCT2 deregulation in human cancers, revealing a molecular link between miR-137, ASCT2 and tumor metabolism.
Citation Format: Xiao Daibiao, Junli Dong, Zihan Zhao, Ping Ren, Cong Li, Yufeng Hu, Jianguo Shi, Hexiu Su, Zhaojing Wang, Hudan Liu, Bo Li, Peng Gao, Guoliang Qing. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1474. doi:10.1158/1538-7445.AM2017-1474
Abstract 1478: Curcumin inhibits epithelial-mesenchymal transition and invasion in breast cancer cells by controlling miR-34a expression
Authors: Gallardo Marcela , Ponce-Cusi Richard , Calaf Gloria M. 
Published: July 2017

Abstract
Breast cancer in advanced stages tends to develop metastases and / or chemoresistance, in both cases therapeutic options are limited and have low probability of success, which represents the biggest obstacle in reducing mortality from this disease. There is a close connection between the Epithelial-Mesenchymal Transition (EMT) process of cancer cells and the acquisition of invasive and metastatic ability. Numerous EMT mediators have been described in cancer and among them miRNAs play a fundamental role in regulating such process, suggesting that it could be a therapeutic target to address this phenotype. Curcumin (diferuloylmethane) is a derivative compound of Curcuma longa that has therapeutic properties in various cancers as blocking initiation and tumor progression through its anti-inflammatory, antioxidant, proapoptotic, antiangiogenic and antimetastatic effects. The role of curcumin on EMT in non-cancerous breast cells MCF-10F and in breast cancer cell lines MCF-7 and MDA-MB-231 was evaluated. This work shows that in all these cell lines curcumin induced the expression of tumor suppressor microRNA miR-34a and repressed the expression of several genes involved in EMT and metastasis as Axl, Slug, Twist, N-cadherin, vimentin, fibronectin, among others. Consequently, curcumin inhibited the migration and invasiveness in these cells, irrespective of the expression of estrogen and progesterone receptors and p53 mutational status. Blockade of miR-34a by transfection with antagomiR-34a inhibited the effect of curcumin on EMT genes and on the migratory/invasive potential of cells indicating that miR-34a plays a central role in the Curcumin-mediated suppression of EMT and invasion. Therefore, results confirm the suppressive effect of curcumin on EMT and invasion in breast cancer cells, showing that such substance exerts this effect by inducing expression of miRNA miR-34a and consequently the repression of several of its target genes. Supported by Tarapacá University, Arica, Chile (GMC).
Citation Format: Marcela Gallardo, Richard Ponce-Cusi, Gloria M. Calaf. Curcumin inhibits epithelial-mesenchymal transition and invasion in breast cancer cells by controlling miR-34a expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1478. doi:10.1158/1538-7445.AM2017-1478
Abstract 148: A dual and selective small molecule inhibitor of EGFR and PI3 kinase shows promising preclinical activity against KRAS and BRAF mutant colorectal tumors
Authors: Maust Joel D. , Ziemke Elizabeth K. , Frankowski-McGregor Christy L. , Ku Jun Beom , Mumby Rachel , Hardiman Karin M. , Whitehead Christopher E. , Sebolt-Leopold Judith S. 
Published: July 2017

Abstract
Agents targeting epidermal growth factor receptor (EGFR) have met with limited success in the clinical management of colorectal cancer (CRC). Mutations in KRAS, BRAF, and PIK3CA are important drivers of resistance to EGFR-targeted therapy. Conversely, EGFR-mediated feedback mechanisms serve to mediate resistance to MEK inhibitor-based treatment of CRC by reactivating MAP kinase signaling. Our central hypothesis is that a dual small molecule inhibitor that potently and selectively targets only EGFR and PI3KA, when combined with a MEK inhibitor, will be highly efficacious against subpopulations of BRAF mutant or KRAS mutant colorectal cancers that are dependent upon these kinase molecules to drive tumor progression. Employing a computational modeling approach, we exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to design small molecules that simultaneously inhibit both kinases in a selective manner. To the best of our knowledge, the lead compound MTX-211, whose binding mode is flipped in PI3K compared to EGFR, represents a first in class selective inhibitor of these two critical oncogenic kinases. MTX-211 exhibits a favorable pharmaceutical and selectivity profile, possessing sub- to low nanomolar potency against both targets, &gt;70% oral bioavailability, strong pharmacodynamic modulation of both EGFR and PI3K signaling, and strong in vivo single agent efficacy against multiple BRAFmt and KRASmt colorectal cancer models, as evidenced by T/C values of 29 to 36% after 10-14 days of oral dosing of 50 mg/kg. A significantly higher degree of in vivo activity is seen when MTX-211 is co-administered with the MEK inhibitor trametinib (&gt;400% increase in survival compared to single agent arms), lending support for this polypharmacology approach over triple drug combination strategies. Based on its promising therapeutic profile, MTX-211 is the focus of an ongoing mouse trial of a large panel of patient-derived xenograft BRAFmt and KRASmt CRC models to inform the design of future human clinical trials.
Citation Format: Joel D. Maust, Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Jun Beom Ku, Rachel Mumby, Karin M. Hardiman, Christopher E. Whitehead, Judith S. Sebolt-Leopold. A dual and selective small molecule inhibitor of EGFR and PI3 kinase shows promising preclinical activity against KRAS and BRAF mutant colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 148. doi:10.1158/1538-7445.AM2017-148
Abstract 1484: Genome wide study reveal microrna based methylation phenotype in oral cancer
Authors: Roy Roshni , Chatterjee Aniruddha , Sarkar Navonil De , Roy Bidyut 
Published: July 2017

Abstract
Introduction: Oral cancer is one of the leading causes of cancer burden in India. Studies over the years have enforced the role of deregulated microRNA expression in oral cancer development and progression. Incidentally not much is known about the cause of microRNA deregulation or to what extent can it be attributed to methylation. Established genome wide microarray platforms like 450K Illumina Bead Chip have probes for very limited number of microRNAs along with restriction on distance of the probes from microRNA transcription start site. We have used genome wide methylation sequencing approach RRBS to get deeper insight on microRNA methylation.
Aim: Genome wide methylation profile of 15 paired oral cancer and adjacent normal tissue was compared to generate a detailed map of microRNA methylation in oral cancer. The methylation results were further correlated to microRNA expression data generated on a subset of these samples.
Methodology: RRBS based global methylation sequencing of 15 pairs of samples was conducted on HiSeq 2500 with an average 10X depth. Analyses were done using DMAP software. Previously generated TLDA based microRNA expression data was used for correlation analysis.
Result: Similar to protein coding genes, microRNAs also showed methylation based clustering. Interestingly majority of methylation hits were more than 2kb upstream of miRNA transcription start site which is generally not considered in known microarrays. Distribution of hypo and hyper methylation sites is different across the various CpG features like cores and shelves as well as across chromosomes. MicroRNAs like mir-181c, miR-99b, miR-23a among others showed significant negative correlation between methylation frequency and expression level. IPA based pathway analysis emphasized repression of apoptosis and cell death pathways along with activation of cell proliferation and colony formation.
Conclusion: Understanding the role of methylation in microRNA deregulation could help us detect and possibly prevent a chain of events, which lead to disrupted pathways eventually leading to cancer, at the onset.
Note: This abstract was not presented at the meeting.
Citation Format: Roshni Roy, Aniruddha Chatterjee, Navonil De Sarkar, Bidyut Roy. Genome wide study reveal microrna based methylation phenotype in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1484. doi:10.1158/1538-7445.AM2017-1484
Abstract 1492: Chemical approaches to development of mitochondrial-targeted Hsp90 inhibitor in anti-cancer therapeutics: Mechanism and structure change of mitochondrial Hsp90
Authors: Hu Sung , Yoon Nam Gu , Kang Byoung Heon 
Published: July 2017

Abstract
Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) which located in mitochondria, is thought to promote tumor cell survival and to reprogram energy metabolism in cancer. Previous studies have demonstrated that the inactivation of TRAP1 selectively induced mitochondrial dysfunction and cell death in cancer cells. Therefore, TRAP1 has been suggested as an emerging target protein for anti-cancer drug development. Isopropyl amine of the Hsp90 inhibitor, PU-H71, was replaced with the mitochondria-targeting moiety, triphenyphosphonium, to produce the mitochondria-accumulating TRAP1 inhibitor, SMTIN-P01. To further optimize SMTIN-P01, we have synthesized several SMTIN-P01 derivatives including TPP-PU-X03 with potent TRAP1 inhibitory activities. TPP-PU-X03 increased TRAP1 ATPase enzyme activity while suppressing chaperone activity, suggesting asymmetric effect on dimeric TRAP1 chaperone functions. Electron microscopic analyses showed TPP-PU-X03 shift TRAP1 conformation from open to close conformation, while other TRAP1 or Hsp90 inhibitors stabilizes open conformation. Importantly, TPP-PU-X03 showed improved mitochondria dysfunction and enhanced cytotoxicity to various cancer cells in vitro and in vivo. Collectively, the structure based optimization of current TRAP1 inhibitors may generate potent anti-cancer drugs with novel mechanisms of action.
Citation Format: Sung Hu, Nam Gu Yoon, Byoung Heon Kang. Chemical approaches to development of mitochondrial-targeted Hsp90 inhibitor in anti-cancer therapeutics: Mechanism and structure change of mitochondrial Hsp90 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1492. doi:10.1158/1538-7445.AM2017-1492
Abstract 1502: The link between NRF2 and mitochondria through the regulation of miR-181c/mitochondria-encoded cytochrome c oxidase subunit-1
Authors: Kwak Mi-Kyoung , Jung Kyeong-Ah , Kim Donghyeok , Lee Sujin 
Published: July 2017

Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is involved in the environmental resistance of cancers by enhancing the antioxidant capacity. In the current study, we investigated the potential link between NRF2 and mitochondrial function in cancer cells. Global miRNA expression analysis of HT29 and HCT116 identified miR-181c as an NRF2-silencing-inducible miRNA, and miR-181c elevation was associated with the decrease in mitochondria-encoded cytochrome c oxidase subunit-1 (MT-CO1), a mitochondrial genome-encoded complex IV subunit of the electron transport chain. As a result of decreased complex IV activity, NRF2-silenced cancer cells exhibited reduced levels of mitochondrial membrane potential (MMP), oxygen consumption rate, and ATP production. Notably, these changes induced adaptive activation of AMP-activated protein kinase-α (AMPKα) and thereby, NRF2-silenced cells were more vulnerable to AMPK inhibitor-induced growth suppression. Similarly, mouse tumor xenografts derived from NRF2-silenced HT29 exhibited MT-CO1 reduction and AMPKα activation, thereby increasing responsiveness to the AMPK inhibitor treatment. Collectively, we showed a novel link of NRF2 to cancer mitochondria and AMPK signaling by elucidating miR-181c/MT-CO1 signaling as an underlying molecular mechanism. These results also suggest that it may an effective strategy to inhibit both NRF2 and AMPK to control adaptive tumor responses.
Citation Format: Mi-Kyoung Kwak, Kyeong-Ah Jung, Donghyeok Kim, Sujin Lee. The link between NRF2 and mitochondria through the regulation of miR-181c/mitochondria-encoded cytochrome c oxidase subunit-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1502. doi:10.1158/1538-7445.AM2017-1502
Abstract 1505: Breast cancer cells treated with mitochondria targeted redox active agents induce mitophagy
Authors: Biel Thomas , Rao Ashutosh 
Published: July 2017

Abstract
Triphenylphosphonium (TPP) conjugated agents induce mitochondrial dysfunction in cancer cells. However, the onset of mitophagy to remove the dysfunctional mitochondria is unknown. Here, a series of mitochondria targeted redox active agents (MTA) that contain TPP were used to investigate mitochondrial dysfunction and mitophagy in MDA-MB-231 cells as compared to MCF-12A cells. Three different MTAs were identified to induced mitochondrial depolarization and enhanced autophagic flux selectively in MDA-MB-231 cells. Mitochondrial reactive oxygen species generation and respiration indicated that MDA-MB-231 cells had a heighten sensitivity to MTA treatments. Using stably expressing mt-mKeima MDA-MB-231 and MCF-12A cell lines, a non-cell type selective decline in mitochondrial alkalinity and altered mitochondrial morphology was detected. Furthermore, FACS analysis of mt-mKeima revealed MTAs induced lysosomal dependent mitochondrial degradation in the presence of Bafilomycin, a lysosomal inhibitor. To confirm MTAs induced mitochondrial autophagy in MDA-MB-231 cells, MitoTracker Red preloaded GFP-LC3 expressing MDA-MB-231 cells were used to identify autophagosomes containing mitochondria using confocal microscopy, in addition to coimmunoprecipitation for the detection of an endogenous autophagy-related protein complex, and immunoblot to for mitochondrial PINK1 accumulation. To translate these in vitro studies to an in vivo rat SST-2 xenograph breast cancer model, tumor mitochondrial extracts from rats treated with MitoQ demonstrated an accumulation of mitochondrial PINK1. Collectively, these data suggest that mitochondrial agents selectively caused mitochondrial depolarization, PINK1 accumulation and mitophagy in MDA-MB-231 cancer cells as compared to MCF-12A healthy cells.
Citation Format: Thomas Biel, Ashutosh Rao. Breast cancer cells treated with mitochondria targeted redox active agents induce mitophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1505. doi:10.1158/1538-7445.AM2017-1505
Abstract 1517: AKT inhibition induces neuroendocrine phenotype in prostate cancer cells
Authors: Chen RuiQi , Li Yinan , Dong Xuesen 
Published: July 2017

Abstract
Androgen receptor (AR) signaling pathway inhibition (ARPI) is the primary treatment for locally advanced, recurrent, or metastatic prostate cancer. While ARPI is effective in short term, a fatal relapse is inevitable. The AKT signaling pathway inhibition has been investigated under multiple ongoing clinical trials as a co-therapeutic target with ARPI. The AKT signaling pathway is targeted due to its role in tumorigenesis, prevalent over-activation, and reciprocal activation upon ARPI in prostate cancer. However, this novel combination therapy may in fact facilitate PCa to progress into one of the most lethal subtypes called neuroendocrine (NE) prostate cancer (NEPC). Specifically, evidence has shown that ARPI contributes to NEPC progression at least in part by down-regulating the expression of RE-1 Silencing Transcription Factor (REST). Loss of REST is a hallmark of NEPC progression because REST functions as a negative master regulator in neurogenesis by suppressing genes required for neural differentiation. Similar to ARPI, our studies found that AKT inhibition reduced REST protein expression and increased NEPC markers in multiple prostate cancer cell lines. We also showed that the loss of REST upon AKT inhibition was through protein degradation mediated by an E3-ubiquitin ligase TRCP, which recognizes a phosphorylated REST degron region to recruit ubiquitins. In vivo ubiquitination assays confirmed the elevated REST ubiquitination after the treatment of PI3K inhibitors. Furthermore, mutations within the REST degron region reversed the TRCP-mediated REST ubiquitination and degradation. Finally, co-treatment of AKT pathway inhibition and ARPI showed aggravated REST depletion and increased NE markers in the prostate cancer cell line LNCaP. Collectively, these findings indicate that AKT pathway inhibition can induce NE phenotype in prostate cancer cells via REST protein degradation. This study may provide a caution to the ARPI/AKT co-target strategy as this strategy can potentially facilitate NEPC development.
Citation Format: RuiQi Chen, Yinan Li, Xuesen Dong. AKT inhibition induces neuroendocrine phenotype in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1517. doi:10.1158/1538-7445.AM2017-1517