bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-126: Replication-associated DNA double-strand breaks and checkpoint abrogation promote gene amplification.
Authors: Kondratova Anna , Marotta Michael , Watanabe Takaaki , Tanaka Hisashi 
Published: August 2014

Abstract
Gene amplification, a copy number increase of genomic segments through DNA rearrangements, drives cancer progression and acquired resistance to anti-cancer drugs. Understanding the cellular processes involved in gene amplification is important to rationally develop management strategies for cancer patients with such aggressive tumors. DNA double-strand breaks (DSBs) are the most dangerous lesions of DNA and often initiate gene amplification. A main cellular process giving rise to DSBs in cancer cells is DNA replication, as cancer cells are under strong replication stress. We hypothesized that failure to repair replication-associated DSBs would result in DNA rearrangements and gene amplification. To test this hypothesis, we suppressed the expression of DNA repair protein MRE11 in mammalian cells. MRE11 is a component of the MRN (Mre11-Rad50-NBS1) complex that repairs DSBs of different origin including those arising during DNA replication. Indeed, knocking down MRE11 resulted in the 10-fold increase in the frequency of gene amplification. DSBs were markedly increased in the MRE11 knockdown cells in the S phase of the cell cycle, suggesting a DNA replication-associated origin of DSBs. Importantly, DSBs continued to be abundant in the M phase, indicating that MRE11 knockdown cells lack both intra-S and G2/M checkpoints. The possibility that checkpoint abrogation could also promote gene amplification was further tested in the I-SceI endonuclease-induced gene amplification system, where checkpoint abrogation by caffeine resulted in the 4-fold increase in amplification frequency. These results provide a proof-of-concept that pharmacological modulation of cell cycle checkpoints can alternate the gene amplification frequency, and may be used to prevent proliferation of cells with gene amplification.
Citation Format: Anna Kondratova, Michael Marotta, Takaaki Watanabe, Hisashi Tanaka. Replication-associated DNA double-strand breaks and checkpoint abrogation promote gene amplification. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-126. doi:10.1158/1538-7445.AM2013-LB-126
Abstract LB-131: Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria.
Authors: Nakamura Yasuyuki , Kamino Hiroki , Sano Hitoya , Arakawa Hirofumi 
Published: August 2014

Abstract
The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. However, when MALM is inhibited, Mieap induces vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulf and degrade the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impairs both MALM and MIV generation. These results suggest that Mieap plays a pivotal role in mitochondrial quality control by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect.
Citation Format: Yasuyuki Nakamura, Hiroki Kamino, Hitoya Sano, Hirofumi Arakawa. Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-131. doi:10.1158/1538-7445.AM2013-LB-131
Abstract LB-132: Frequent inactivation of the p53/Mieap/BNIP3 mitochondrial quality control pathway in gastric cancer.
Authors: Sano Hitoya , Kamino Hiroki , Nakamura Yasuyuki , Yoshida Masaki , Murai Ryuya , Saito Yuri , Futamura Manabu , Yoshida Kazuhiro , Arakawa Hirofumi 
Published: August 2014

Abstract
Recently, we discovered a novel mechanism for mitochondrial quality control (MQC), in which Mieap, a p53-inducible protein, controls MQC by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole) generation, respectively (1, 2). We also reported that two mitochondrial outer membrane proteins, BNIP3 and NIX, are essential mediators of the MALM (2, 3). To examine the role of Mieap-regulated MQC pathway in tumorigenesis, we analyzed the status of p53, Mieap, BNIP3, and NIX in 50 cases of primary gastric cancer. Of the 50 patients, Mieap and BNIP3 promoter methylation was observed in 2 (4%) and 29 (58%) patients, respectively. A p53 mutation was detected in 2 (10%) of the 20 patients with either Mieap or BNIP3 promoter methylation whereas it was found in 3 (15.8%) of the 19 patients with neither Mieap nor BNIP3 promoter methylation, implying that the p53/Mieap/BNIP3 MQC pathway is inactivated in at least 70% of gastric cancer cases. In a colorectal cancer cell line, hypoxia induced MALM. Knockdown of p53, Mieap, or BNIP3 in the cell line severely inhibited hypoxia-induced MALM, leading to the accumulation of unhealthy mitochondria and increased mitochondrial reactive oxygen species (mtROS) generation. Furthermore, the mtROS dramatically enhanced cancer migration and invasion in hypoxic conditions. These results suggest that the p53/Mieap/BNIP3 MQC pathway plays a tumor-suppressive role in gastric cancer.
1. Miyamoto Y et al. PLoS ONE 6: e16054, 2011
2. Kitamura N et al. PLoS ONE 6: e16060, 2011
3. Nakamura Y et al. PLoS ONE 7: e30767, 2012
Citation Format: Hitoya Sano, Hiroki Kamino, Yasuyuki Nakamura, Masaki Yoshida, Ryuya Murai, Yuri Saito, Manabu Futamura, Kazuhiro Yoshida, Hirofumi Arakawa. Frequent inactivation of the p53/Mieap/BNIP3 mitochondrial quality control pathway in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-132. doi:10.1158/1538-7445.AM2013-LB-132
Abstract LB-135: Stanniocalcin 2 attenuates tumor cell proliferation but suppresses apoptosis in nutrient-deprived conditions.
Authors: Qie Shuo , Tian Lifeng , Wang Chenguang , Sang Nianli 
Published: August 2014

Abstract
High levels of stanniocalcin2 (STC2), a member of the STC secreted glycoprotein family, correlates with tumor progression and poor prognosis. It has been reported that STC2 is over-expressed in response to various stresses, including hypoxia, endoplasmic reticulum stress, oxidative stress and irradiation. Glutamine (Gln) and glucose (Glc) are important nutrients for tumor cells, playing important roles as nitrogen and carbon sources to meet the bioenergetic, biosynthetic and reductive needs. Defective blood supply in solid tumors may result in nutrient insufficiency, including Gln and Glc insufficiency. It remains unknown how tumor cells respond to Gln- and Glc- insufficient microenvironment and regulate their viability and proliferation. Using gene profiling analysis with microarrays, we have identified STC2 as one of the most up-regulated genes in response to either Gln- or Glc- deprivation. We confirm that Gln-deprivation stimulates STC2 expression at both mRNA and protein levels in various human tumor cells by quantitative reverse transcription-real-time PCR and Western blot, respectively. Furthermore, we find that Gln-insufficiency activates both nuclear factor-κB (NF-κB) and ATF4 signaling pathways, which synergistically up-regulates STC2. Finally, we demonstrate that up-regulation of STC2 attenuates tumor cell proliferation but reduces apoptosis in Gln-insufficient conditions. These findings suggest a novel model that STC2 reprograms the priority of tumor cells from rapid proliferation to survival under stress conditions, indicating that STC2 may be a novel target for cancer therapy.
Citation Format: Shuo Qie, Lifeng Tian, Chenguang Wang, Nianli Sang. Stanniocalcin 2 attenuates tumor cell proliferation but suppresses apoptosis in nutrient-deprived conditions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-135. doi:10.1158/1538-7445.AM2013-LB-135
Abstract LB-154: COX-2 as a mediator of oncogenic PKCε in prostate cancer.
Authors: Garg Rachana , Lal Priti , Blando Jorge , Benavides Fernando J. , Feldman Michael D. , Smyth Emer M. , Kazanietz Marcelo G. 
Published: August 2014

Abstract
Protein kinase C epsilon (PKCε), a member of the PKC family of phorbol ester/diacylglycerol receptors, is up-regulated in many human cancers, including prostate cancer. We recently demonstrated that PKCε is an essential mediator of NF-κB activation in prostate cancer (Garg et al., JBC, 287 (44), 37570–37582, 2012). Cyclooxygenase-2 (COX-2), a well-known NF-κB regulated gene, has been reported to be up-regulated in a number of human cancers, including metastatic prostate cancer. As PKCε plays an important role in prostate cancer cell survival and cooperates with other oncogenic insults, herein we aim to determine if PKCε regulates COX-2 activation during prostate tumorigenesis. PKCε RNAi depletion diminishes TNFα- or LPS-induced COX-2 mRNA expression in LNCaP prostate cancer cells and constitutive COX-2 levels from PC3 cells. Conversely, PKCε overexpression by adenoviral means potentiates TNFα or LPS-induced COX-2 expression in LNCaP cells. Notably, transgenic overexpression of PKCε in the mouse prostate causes preneoplastic lesions with elevated COX-2 levels. Interestingly, when we intercrossed the prostate-specific PKCε transgenic mice with mice haploinsufficient for Pten, a common genetic alteration in human prostate cancer, the resulting compound mutant mice (PB-PKCε;Pten+/− mice) developed fully invasive adenocarcinoma with NF-κB hyperactivation and high COX-2 levels. Likewise, stable overexpression of PKCε in mouse prostate epithelial cell lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion, led to significant enhancements in cell proliferation, motility and invasiveness as well as in LPS-induced COX-2 mRNA expression compared to the respective control cells, and this effect is more pronounced in CaP8 cells. Studies using human prostate tumors revealed a co-existence of PKCε overexpression, NF-κB hyperactivation, and COX-2 up-regulation. Lastly, treatment of PKCε overexpressing P8 or CaP8 cells with the selective COX-2 inhibitor NS398 caused a pronounced growth inhibition. Overall, our study identified COX-2 as a PKCε-regulated gene. Our results suggest that COX-2 as a potential mediator of PKCε oncogenesis in prostate cancer, particularly in the context of Pten loss.
Citation Format: Rachana Garg, Priti Lal, Jorge Blando, Fernando J. Benavides, Michael D. Feldman, Emer M. Smyth, Marcelo G. Kazanietz. COX-2 as a mediator of oncogenic PKCε in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-154. doi:10.1158/1538-7445.AM2013-LB-154
Abstract LB-187: Dietary energy balance modulation of Kras- and Ink4a/Arf+/-driven pancreatic cancer: the role of insulin-like growth factor-1.
Authors: Lashinger Laura M. , Harrison Lauren M. , Rasmussen Audrey J. , Logsdon Craig D. , Fischer Susan M. , McArthur Mark J. , Hursting Stephen D. 
Published: August 2014

Abstract
New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant murine spontaneous and orthotopically transplanted models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF) 1—dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arflox/+ mice, calorie restriction, versus overweight- or obesity-inducing diet regimens, decreased serum IGF-1, tumoral Akt/mammalian target of rapamycin (mTOR) signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC); and increased pancreatic tumor-free survival by 50%. Serum IGF-1, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-1—deficient mice (versus wild-type mice), and rescued with IGF-1 infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a/Arf deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-1 and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.
Citation Format: Laura M. Lashinger, Lauren M. Harrison, Audrey J. Rasmussen, Craig D. Logsdon, Susan M. Fischer, Mark J. McArthur, Stephen D. Hursting. Dietary energy balance modulation of Kras- and Ink4a/Arf+/-driven pancreatic cancer: the role of insulin-like growth factor-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-187. doi:10.1158/1538-7445.AM2013-LB-187
Abstract LB-189: BIRC5 (Survivin) is a prognostic biomarker and potential drug target for patients with malignant peripheral nerve sheath tumors.
Authors: Kolberg Matthias , Høland Maren , Ågesen Trude H. , Skotheim Rolf I. , Bjerkehagen Bodil , Hall Kirsten S. , Mertens Fredrik , Smeland Sigbjørn , Lev Dina C. , Davidson Ben , Lote Ragnhild A. 
Published: August 2014

Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue cancer with high mortality, and there are currently few therapeutic options beyond surgery. We have performed a transcriptome study of 30 MPNSTs and 8 neurofibromas and used a tissue microarray (TMA) with cores from 63 MPNSTs to identify candidate genes and proteins for targeted therapy. The anti-apoptotic gene BIRC5 was one of the most significantly upregulated genes in MPNST vs neurofibroma. This gene is located on the long arm of chr 17, and we have previously shown common gains of 17q sequences and pinpointed BIRC5 as a potential target in MPNSTs. Recently BIRC5 was also identified as a potential drug target. Here, we show that MPNST patients with above median BIRC5 mRNA expression levels had significantly worse 5-year disease-specific survival (DSS: 26%) than patients with below median mRNA levels (DSS: 87%) (P=.0003). Immunohistochemical analyses showed that increased protein expression is also associated with a worse disease outcome (P=.02). We recently performed a meta-analysis on survival for NF1 associated MPNST and sporadic MPNST based on 1800 patients which suggest no difference between these groups. Our data suggest that MPNST patients who present tumors with high expression of BIRC5 might benefit from targeted treatment directed against BIRC5.
Citation Format: Matthias Kolberg, Maren Høland, Trude H. Ågesen, Rolf I. Skotheim, Bodil Bjerkehagen, Kirsten S. Hall, Fredrik Mertens, Sigbjørn Smeland, Dina C. Lev, Ben Davidson, Ragnhild A. Lote. BIRC5 (Survivin) is a prognostic biomarker and potential drug target for patients with malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2013-LB-189
Abstract LB-212: Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.
Authors: He Lei , Torres-Lockhart Kristine , Forster Nicole , Ramakrishnan Saranya , Greninger Patricia , Garnett Mathew J. , McDermott Ultan , Rothenberg S. Michael , Benes Cyril , Ellisen Leif 
Published: August 2014

Abstract
Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the HDAC inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3 mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.
Citation Format: Lei He, Kristine Torres-Lockhart, Nicole Forster, Saranya Ramakrishnan, Patricia Greninger, Mathew J. Garnett, Ultan McDermott, S. Michael Rothenberg, Cyril Benes, Leif Ellisen. Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-212. doi:10.1158/1538-7445.AM2013-LB-212
Abstract LB-217: A gene signature that predicts deficiency of homologous recombination DNA repair.
Authors: Peng Guang , Mills Gordon , Lin Shiaw-Yih 
Published: August 2014

Abstract
DNA repair pathways play a fundamental role to maintain genomic stability. Defects in specific DNA repair pathways predispose to cancer development, but also provide therapeutic opportunities: for example, poly-ADP ribose polymerase (PARP) inhibitors are synthetically lethal with cancer cells, which are defective in homologous recombination (HR)-mediated DNA repair, such as BRCA1/BRCA2-deficient tumors. However, recent clinical trials of PARP inhibitors have shown rather disappointing results, particularly in the treatment of triple-negative breast cancer (TNBC), which has a molecular phenotype similar to that of BRCA-deficient breast cancer. As a targeted therapy, the clinical success of PARP inhibitors is dependent on identifying cancer cells with HR repair deficiency. Thus the observations of PARP inhibitors from clinical trials raise a key question: Can we identify a molecular signature of HR repair deficiency in cancer cells?
To answer this question, we utilized the gene expression profiling approach to measure the cellular transcriptional reprograming in HR-deficient cell lines. By analyzing the molecular changes of transcriptional landscape, we identified an HR-defect gene signature that predicted HR repair deficiency in cells, predicted clinical outcomes of multiple human cancers, and predicted sensitivity of human cancer cells to PARP inhibitors. HR repair deficiency leads to genomic instability and often promotes accumulation of additional mutations. Our gene signature analysis further revealed that combinatorial effects of co-existing genetic changes such as loss of both BRCA1 and PTEN may extensively rewire the HR repair network and confer resistance to PARP inhibitor treatment. Moreover, to combat PARP inhibitor resistance, we successfully used our HR-defect gene signature as a drug discovery tool and found that TTK, mTOR and PI3K inhibitors could induce HR repair deficiency and sensitize cancer cells to PARP inhibitor treatment. Collectively, our findings demonstrate that transcriptional signature can be used to define the functional status of the HR repair network in cells.
In summary, our study identifies a gene signature of HR repair deficiency, which provides a novel network view of the DNA repair process. In addition to using our gene signature as a prognostic marker for multiple cancers including breast, ovarian and lung cancer, our findings potentially have a significant impact on predicting responsiveness and overcoming resistance to targeted therapeutic regimens with DNA repair inhibitors such as PARP inhibitors.
Citation Format: Guang Peng, Gordon Mills, Shiaw-Yih Lin. A gene signature that predicts deficiency of homologous recombination DNA repair. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2013-LB-217