bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4322: The landscape of mitochondrial DNA mutations in human cancer
Authors: Ju Young Seok , Alexandrov Ludmil , Gerstung Moritz , Martincorena Inigo ,   ICGC Breast Cancer Group; ICGC Chronic Myeloid Disorders Group; ICGC Prostate Cancer Group, Stratton Mike , Campbell Peter J. 
Published: May 2015

Abstract
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of human cancers. Although mitochondria in cancer cells have important roles in energy metabolism and survival, the origins and impact of somatic mutations in mitochondrial DNA (mtDNA) are unclear. Here, we provide a comprehensive analysis of somatic alterations in cancer mitochondria from 1,675 genome sequences across 31 tumor types. We identified 1,907 somatic substitutions which were mainly C:G&gt;T:A and T:A&gt;C:G. These mutations exhibited dramatic replicative strand bias, being almost all C&gt;T and A&gt;G on the mitochondrial heavy strand. This strand-asymmetric mitochondrial mutational signature is different from those found in nuclear cancer genomes but is similar to processes shaping human mtDNA sequence over evolutionary time. The number of mtDNA mutations showed considerable heterogeneity across tumor types, being significantly higher in tumors from gastrointestinal and hepatobiliary systems. With respect to selection, observed missense mutations were nearly neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation showed evidence of negative selection and were more frequently heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.
Citation Format: Young Seok Ju, Ludmil Alexandrov, Moritz Gerstung, Inigo Martincorena, ICGC Breast Cancer Group; ICGC Chronic Myeloid Disorders Group; ICGC Prostate Cancer Group, Mike Stratton, Peter J. Campbell. The landscape of mitochondrial DNA mutations in human 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 4322. doi:10.1158/1538-7445.AM2014-4322
Abstract 4334: Greater resistance of mutant p53 tumor cells to hypoxia or chloroquine with glucose or pyruvate supplementation is diminished under glucose starvation
Authors: Rieber Manuel 
Published: May 2015

Abstract
BACKGROUND. Poorly vascularized solid tumors are exposed to regions of low oxygen and glucose deprivation. These restrictions may promote either defensive autophagy or cell death through excessive reactive oxygen species (ROS), mediated by activated NADPH oxidases (NOX) which transport electrons from NADPH on the cytoplasmic side of plasma membranes to reduce molecular oxygen at the extracellular space, increasing superoxide anion radical (O2•-). .OBJECTIVES. To investigate in genetically-matched human melanoma cells with wt or mutant p53, responses to: a) autophagy inhibitor chloroquine and to glucose-lowering metformin or to hypoxia in glucose-supplemented medium; b) pyruvate in glucose-free medium under normoxia or hypoxia; c) sub-physiological glucose. EXPERIMENTAL. Responses to normoxia or hypoxia were assesed by live-dead fluorometric assays, or by crystal violet staining of surviving cells. Mechanisms influencing response to glucose limitation were studied by specific immune blotting. RESULTS. Lower susceptibility to chloroquine ± metformin involving greater basal AMPK activation was seen in physiological 5 mM glucose in mutant p53 cells. These cells were also preferentially protected from prolonged hypoxia by glucose supplementation or by pyruvate supplementation of glucose-free medium under normoxia, but not under hypoxia. Sub-physiological glucose without pyruvate induced apoptosis-associated PARP cleavage irrespective of p53 status. However, treatment with impermeable exogenous superoxide dismutase (SOD) to remove extracellular superoxide signalling across cell membranes, preferentially counteracted PARP cleavage only in wt p53 cells with lower LDHA expression after 48 hr in 2.5 mM glucose. CONCLUSIONS. Glucose availability increases resistance to hypoxia or to chloroquine ± metformin in mutant p53 cells. However, glucose starvation promotes toxicity linked to extracellular (O2•-), preferentially in mutant p53 cells.
Citation Format: Manuel Rieber. Greater resistance of mutant p53 tumor cells to hypoxia or chloroquine with glucose or pyruvate supplementation is diminished under glucose starvation. [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 4334. doi:10.1158/1538-7445.AM2014-4334
Abstract 4345: Dysregulated miR-205 signaling promotes symmetric division of self-renewing mammary stem cells and mammary tumorigenesis
Authors: Wu Meng-Ju , Chao Chi-Hong , Chang Chao-Ching , Chang Chun-Ju 
Published: May 2015

Abstract
Epigenetic control plays a key role in regulation of tumorigenesis in response to the microenvironmental stimuli, however, the regulatory mechanism involved in the process is largely unclear. We now report that a critical epigenetic regulator miR-205 is repressed by Jagged1, a ligand shown to be secreted from the tumor stroma, to promote the cancer stem cell phenotype. Loss of miR-205 in mammary epithelial cells leads to epithelial-mesenchymal transition, disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, mice deficient of miR-205 spontaneously develop mammary lesions, and activation of miR-205 significantly diminishes the breast cancer stemness. These data provides the first evidence to link microenvironment and microRNA regulation to the disrupted epithelial polarity and aberrant stem cell division, leading to an expansion of the stem cell population and tumorigenesis. Together, this study elucidates a new role for miR-205 in regulation of stem cell fate, providing a promising therapeutic target to eradicate the genesis of breast cancer.
Citation Format: Meng-Ju Wu, Chi-Hong Chao, Chao-Ching Chang, Chun-Ju Chang. Dysregulated miR-205 signaling promotes symmetric division of self-renewing mammary stem cells and mammary tumorigenesis. [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 4345. doi:10.1158/1538-7445.AM2014-4345
Abstract 4351: Targeting miRNA-driven aggressive behavior of pancreatic cancer stem cells by a novel drug
Authors: Bao Evan , Azmi Asfar , Zhang Ellen , Ali Shadan , Ahmad Aamir , Zaiem Feras , Bao Bin , Sarkar Fazlul H. 
Published: May 2015

Abstract
Pancreatic cancer (PC) is a lethal malignant disease, which is in part due to lack of early detection biomarkers. Once diagnosed, the majority of PC patients are already in advanced stages. Currently there are no effective treatments in improving the overall survival. Therefore, the majority of PC patients die within 5-6 months due to therapeutic resistance and early metastatic disease. Recently, a sub-population of cancer stem cells (CSCs) (&lt;0.1%) have been identified from many different tumors including PC, and these cells are believed to be responsible for treatment resistance, tumor recurrence and metastasis. Many studies have shown that the existence of CSCs has important clinical implications because CSCs are involved in cell migration/invasion, drug resistance, and metastasis, which leads to poor clinical outcome. Therefore, selective killing or complete elimination of CSCs by novel approaches would likely become newer treatment strategy for PC in the improvement of overall survival. However, the regulation of CSC characteristics during tumor development and progression has not been well understood. In this study, cell and molecular biology techniques were used to investigate the CSC characteristics and its regulation to find a new effective approach for the treatment of PC. We found that cancer stem-like cells (CSLCs) which is reminiscent of CSCs isolated from human PC cell line, MiaPaCa-2 cells as triple-marker positive cells (CD44+/CD133+/EpCAM+ cells) cells displayed aggressive phenotypes, such as increased clonogenicity, cell migration, and self-renewal capacity, along with over-expression of CSC marker microRNAs (miRNAs) such as miR-21 and miR-210. Under-expression of miR-21 and miR-210 by transfection of anti-miRNAs led to decreased clonogenicity, cell migration and self-renewal capacity, along with reduced expression of CSC-associated markers/mediators such as CD44, EpCAM, EZH2, Notch-1, and Snail in CSLCs. Similarly, under-expression of CSC-associated mediator Notch-1 led to decreased cell migration, self-renewal capacity, and expression of EpCAM and Snail in CSLCs. Finally, CDF, a novel synthetic small molecule showed reduced aggressive behavior of CSLCs such as cell survival/growth, migration, clonogenicity, self-renewal capacity, and decreased expression of miR-21 and miR-210. From these results, we conclude that CDF may serve as an effective anti-tumor agent via targeting miRNA-driven aggressive behavior of CSLCs.
Citation Format: Evan Bao, Asfar Azmi, Ellen Zhang, Shadan Ali, Aamir Ahmad, Feras Zaiem, Bin Bao, Fazlul H. Sarkar. Targeting miRNA-driven aggressive behavior of pancreatic cancer stem cells by a novel drug. [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 4351. doi:10.1158/1538-7445.AM2014-4351
Abstract 4360: Hypoxia-induced miR-372 targets p62 to affect the progression of oral carcinoma
Authors: Yeh Li-Yin , Lin Shu-Chun , Liu Chung-Ji , Wong Yong-Kie , Chang Kuo-Wei 
Published: May 2015

Abstract
Oral squamous cell carcinoma (OSCC) is one of the prevalent neoplasms worldwide. Recent studies have shown that miRNAs were involved in the pathogenesis of various human malignancies, which function by post-transcriptional down-regulation of target genes. Also, hypoxia is a feature of most tumors and plays an important role in regulating tumor progression and resistance to therapy. In our previous study, we found that miR-372 was highly expressed in OSCC tissues. Other studies have shown the oncogenic roles of miR-372 in regulating the cell cycle and apoptosis in tumor cells by targeting different targets. This study identified that miR-372 was up-regulated by hypoxia in OSCC cells. The plasma level of miR-372 in OSCC patients significantly increased with the advance of OSCC. p62 is a multidomain protein that interacts with key components to drive diverse impacts on signaling regulation including detoxification pathway. Using in silico prediction modules, qRT-PCR analysis, Western blot analysis, reporter assay and exogenous expression construct, we discovered that p62 was a novel target of miR-372. Ectopic miR-372 expression and knockdown of p62 both enhanced the migration of OSCC cells, but it did not affect the proliferation of OSCC cells. Furthermore, we demonstrated that p62 was able to induce the expression of phase II enzyme NQO1, which resulted in the attenuation of reactive oxygen species and migration in OSCC cells. Furthermore, correlation among the expression of miR-372, p62 and NQO1 was found in OSCC tissues. This study concludes that hypoxia-induced miR-372 expression modulates the progression of OSCC by targeting p62, which disrupts the ROS homeostasis in tumor cells.
Citation Format: Li-Yin Yeh, Shu-Chun Lin, Chung-Ji Liu, Yong-Kie Wong, Kuo-Wei Chang. Hypoxia-induced miR-372 targets p62 to affect the progression of oral carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2014-4360
Abstract 4364: Posttranscriptional regulation of tetraspanins CD151 & CD9 in breast & prostate cancers
Authors: Bond Danielle R. , Passfield Crystal , Cairns Murray , Ashman Leonie K. , Weidenhofer Judith 
Published: May 2015

Abstract
Rationale
The tetraspanins CD151 & CD9 are known to play a prominent role in cancer progression by modulating cell adhesion and migration/invasion. CD151 is commonly overexpressed (metastasis enhancer) and tends to predict poor prognosis in many solid malignancies, whereas the metastasis suppressor CD9 is typically down-regulated which correlates with poor patient outcomes. However, progress in developing CD151 and CD9 as prognostic biomarkers & therapeutic targets has been hampered by a lack of understanding of how they are regulated in normal cells and how they are deregulated in cancers.
Objective
Many micro-RNAs are deregulated in prostate and breast cancers. Bio-informatic analysis has identified 250 miRNAs that potentially regulate CD151 or CD9. Therefore, we investigated whether miRNAs regulate CD151 and CD9 in a range of normal and cancerous breast and prostate cell lines in vitro.
Methods & Results
A dual luciferase reporter assay using the 3′UTR of CD151 and CD9 provided evidence that breast & prostate cancer cell lines endogenously express miRNA that regulate tetraspanins and that the extent of regulation varies across the cell lines. Analysis of miRNA expression in normal and cancer cell lines using miRNA arrays and qPCR has confirmed that some miRNAs which are predicted to target CD9, are up-regulated in many prostate and/or breast cancer cell lines compared to non-tumourigenic cells. Furthermore, miRNAs were identified with altered expression that were predicted to target CD151. These miRNA have also been shown to directly regulate CD151 or CD9 using the dual luciferase 3′UTR reporter assay with miRNA mimics.
Conclusion
Altered miRNA expression may contribute to prostate and breast cancers by manipulating tetraspanins to allow cancer progression and metastasis. Therefore, miRNA may be effective prognostic and/or therapeutic targets for prostate and breast cancers in the future.
Citation Format: Danielle R. Bond, Crystal Passfield, Murray Cairns, Leonie K. Ashman, Judith Weidenhofer. Posttranscriptional regulation of tetraspanins CD151 & CD9 in breast & prostate cancers. [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 4364. doi:10.1158/1538-7445.AM2014-4364
Abstract 4388: Targeted VHL activation by RNAa inhibits renal cell carcinoma
Authors: Kang Jong Soon , Kang Moo Rim , Yun Jieun , Oh Soo Jin , Park Ki Hwan , Lee Chang Woo 
Published: May 2015

Abstract
Von Hippel Lindau (VHL) is a tumor suppressor protein classically known to target the α subunit of hypoxia inducible factor (HIF) for proteasomal degradation. Emerging evidence has underscored a novel role for VHL in both cell cycle regulation and extracelluar matrix assembly. Recent studies have reported that chemically synthesized small duplex RNAs complementary to target promoter sequence, also known as small activating RNA (saRNA), can specifically induce gene expression in cancer cells, which might be associated with epigenetic changes and exhibited long-lasting gene activation for nearly 2 weeks. In the present study, we designed 5 candidate dsRNAs (dsVHL-58, dsVHL-93, dsVHL-395, dsVHL-515 and dsVHL-675) targeted for the VHL promoter at sites ranging from -675 to -58 relative to the transcription start site. Compared with controls, dsVHL-675 induced VHL expression by approximately 10-fold in renal cell carcinoma 769-P (VHL methylated) cells. Transfection of a dsVHL-675 into 769-P cells significantly inhibited cell proliferation in dose dependent manner. In addition, single transfection of dsVHL-675 induced VHL gene expression for 14 days. Functional analysis of dsVHL-675 transfected cells revealed that dsVHL-675 induced apoptosis by activating caspase 3 in dose dependent manner. Knockdown experiments confirmed that induction of apoptosis by dsVHL-675 required Ago2 and TNRC6A. This study suggests that targeted activation of VHL by dsVHL-675 may be explored as a novel therapy for the treatment of renal cell carcinoma.
Citation Format: Jong Soon Kang, Moo Rim Kang, Jieun Yun, Soo Jin Oh, Ki Hwan Park, Chang Woo Lee. Targeted VHL activation by RNAa inhibits renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4388. doi:10.1158/1538-7445.AM2014-4388
Abstract 4417: Targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
Authors: Rossanese Olivia W. , Burns Michael C. , Sun Qi , Daniels R. Nathan , Camper DeMarco V. , Kennedy J. Phillip , Phan Jason , Olejniczak Edward T. , Lee Taekyu , Waterson Alex G. , Fesik Stephen W. 
Published: May 2015

Abstract
Aberrant activation of Ras, by mutation or constitutively active upstream kinases, occurs in nearly 30% of all human cancers, rendering Ras one of the most validated targets in cancer drug discovery. Historically, the direct inhibition of Ras with small molecules has proven extremely difficult. Here we report the discovery of compounds that bind to a unique pocket on the Ras:SOS:Ras complex, which increase the rate of SOScat-catalyzed nucleotide exchange in vitro and modulate Ras signaling pathways in cells. X-ray crystallography reveals that the molecules bind in a hydrophobic pocket in the CDC25 domain of SOS, adjacent to the Switch II region of Ras. Structure-based mutational analyses confirmed the functional relevance of this binding site and demonstrated that it is essential for compound activity. Consistent with their increased exchange activity in vitro, these molecules increase Ras-GTP levels in cells. However, the compounds inhibit ERK and AKT phosphorylation; the ERK inhibition at high concentrations is accompanied by an increase of p-ERK levels at lower compound concentrations. These molecules represent a unique tool to study the acute activation of Ras and highlight a novel pocket on SOS that may be exploited to modulate Ras signaling.
Citation Format: Olivia W. Rossanese, Michael C. Burns, Qi Sun, R. Nathan Daniels, DeMarco V. Camper, J. Phillip Kennedy, Jason Phan, Edward T. Olejniczak, Taekyu Lee, Alex G. Waterson, Stephen W. Fesik. Targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. [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 4417. doi:10.1158/1538-7445.AM2014-4417
Abstract 4423: Somatic mutations in the insulin-like growth factor-1 and insulin receptors found in cancer genomes result in constitutive activation of the receptor kinases
Authors: Greer Ann , Hillerman Stephen , Chang Han , Wong Tai Wai 
Published: May 2015

Abstract
Somatic mutations in receptor tyrosine kinases have been shown to be a mechanism by which tumor cells subvert signaling pathways to drive deregulated cell proliferation. The insulin-like growth factor 1 receptor (IGF-1R) and the related insulin receptor (InsR) regulate cell metabolism and cell proliferation by phosphorylating two related adapter proteins called insulin receptor substrates (IRS1/2). The IRS proteins are unique to the IGF-1R/InsR signaling pathway, and are recruited to the receptors by virtue of the interaction between the SH2 sequences of IRS1/2 and tyrosine auto-phosphorylation sites on the receptors. The complete sequence determination of cancer genomes has now made it possible to assess the extent of mutation in components of the IGF-1R/InsR signaling pathway. Analyses of The Cancer Genome Atlas (TCGA) data from colorectal cancer patients revealed that &gt;25% of the tumor type have copy number gain in the genes encoding IRS2 or the ligand IGF2. These observations suggest a role for the IGF-1R/InsR signaling pathway in the pathobiology of colorectal cancer. To better understand the extent to which the IGF-1 and insulin receptors may be oncogenic drivers, we surveyed the TCGA data sets for somatic mutations in IGF-1R and InsR. To date, over 50 non-synonymous missense mutations in each of the two receptors have been identified across multiple tumor types. Mutations occur in both the extracellular and intracellular sequences, and few mutations are recurrent. cDNA containing IGF-1R and InsR mutations were analyzed for their intrinsic kinase activities. A number of mutations in the kinase domains resulted in constitutive activation of the receptor kinases, in a similar manner to what has been observed with other receptor tyrosine kinases. Effects of these mutations on the ability of the receptors to drive signal transduction and cell proliferation have been analyzed and will be reported. Results of these studies have further validated a role for the IGF-1R and InsR signaling pathway in cancer.
Citation Format: Ann Greer, Stephen Hillerman, Han Chang, Tai Wai Wong. Somatic mutations in the insulin-like growth factor-1 and insulin receptors found in cancer genomes result in constitutive activation of the receptor kinases. [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 4423. doi:10.1158/1538-7445.AM2014-4423
Abstract 4429: Loss of function Cbl-c mutations in solid tumors
Authors: Kales Stephen C. , Ryan Philip E. , Nau Marion M. , Green Jeffrey E. , Lipkowitz Stanley 
Published: May 2015

Abstract
Receptor Tyrosine Kinase (RTK) signaling is essential for normal biological processes and disruption of this regulation can lead to tumor initiation and progression. Cbl proteins are a family of RING finger ubiquitin ligases that negatively regulate a variety of RTKs, including EGFR, MET, RET and components of the TCR pathway. Recent studies have identified a growing number of Cbl mutations associated with human myeloid neoplasias and epithelial tumors. Cbl-c is the most recently identified human Cbl protein and is expressed exclusively in epithelial cells. Recently, a novel cDNA has been isolated from the ductal carcinoma of a mouse mammary cancer model. This mutant has a deletion in the catalytic domain of Cbl-c, thereby resembling known Cbl family mutations associated with myeoloid neoplasias. Genomic analysis of both parental and transgenic lines shows no evidence of germline mutation indicating that this mutation is likely a somatic mutation. In overexpression studies, this mutant cDNA fails to mediate ubiquitination and degradation of activated EGFR and, acting as a dominant negative, enhances cell transformation. Furthermore, data mining reveals several Cbl family mutations associated with solid tumors in humans. Subsequent cell-based analysis demonstrates a similar loss of E3 function in some of these human mutations. Through subsequent analysis of transforming capacity and signal pathway regulation, we are assessing interacting partners of Cbl-c and the potential role of these mutations in tumorigenesis.
Citation Format: Stephen C. Kales, Philip E. Ryan, Marion M. Nau, Jeffrey E. Green, Stanley Lipkowitz. Loss of function Cbl-c mutations in solid tumors. [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 4429. doi:10.1158/1538-7445.AM2014-4429