bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2402: Antitumor effect of a poly (ADP-ribose) polymerase (PARP) inhibitor in endometrial carcinoma cell lines
Authors: Miyasaka Aki , Oda Katsutoshi , Ikeda Yuji , Kashiyama Tomoko , Koso Takahiro , Inaba Kanako , Fukuda Tomohiko , Makii Chinami , Asada Kayo , Kurikawa Reiko , Hiraike Osamu Wada , Sone Kenbun , Uehara Yuriko , Matsumoto Yoko , Arimoto Takahide , Kuramoto Hiroyuki , Yano Tetsu , Kawana Kei , Osuga Yutaka , Fujii Tomoyuki 
Published: May 2015

Abstract
The loss of PTEN is the most frequent genetic aberration in endometrial cancer. One of the phosphatase-independent roles of PTEN is associated with homologous recombination (HR) in the nucleus. Poly (ADP-ribose) polymerase (PARP) plays a key role in the repair of DNA single-strand breaks, and a PARP inhibitor induces synthetic lethality in cancer cells with HR deficiency. We examined the anti-tumor activity of olaparib, a PARP inhibitor, and its correlation between the sensitivity and status of PTEN in a panel of endometrial cancer cell lines.
Methods
The response to olaparib was evaluated using a clonogenic assay with SF50 values (concentration to inhibit cell survival to 50%) in 16 endometrial cancer cell lines. The effects of PTEN introduction on the sensitivity of cells to olaparib and ionizing radiation (IR) exposure were compared between parental HEC-6 (PTEN-null) and HEC-6 PTEN+ (stably expressing wild-type PTEN) cells by clonogenic assay, foci formation of RAD51 and γH2AX, and induction of cleaved PARP.
Results
The SF50 values were 100 nM or less in six of the 16 (38%: sensitive) cell lines; whereas, SF50 values were 1,000 nM or more in five of the 16 (31%: resistant) cell lines. PTEN mutations were not associated with sensitivity to olaparib (Mutant [n = 12]: 995 ± 1,096 nM; Wild-type [n = 4]: 144 ± 91 nM, p = 0.17 by Student'st test). RAD51 expression was observed broadly and was not associated with PTEN status in the 16 cell lines. The number of colonies in the clonogenic assay, the foci formation of RAD51 and γH2AX, and the induction of apoptosis were not affected by PTEN introduction in the HEC-6 PTEN+ cells. The expression level of nuclear PTEN was not elevated within 24 h following IR in the HEC-6-PTEN+ cells.
Conclusions
Our results suggest that olaparib, a PARP inhibitor, is effective on certain endometrial cancer cell lines. The inactivation of PTEN might not affect the DNA repair function. Predictive biomarkers are warranted to utilize olaparib in endometrial cancer.
Citation Format: Aki Miyasaka, Katsutoshi Oda, Yuji Ikeda, Tomoko Kashiyama, Takahiro Koso, Kanako Inaba, Tomohiko Fukuda, Chinami Makii, Kayo Asada, Reiko Kurikawa, Osamu Wada Hiraike, Kenbun Sone, Yuriko Uehara, Yoko Matsumoto, Takahide Arimoto, Hiroyuki Kuramoto, Tetsu Yano, Kei Kawana, Yutaka Osuga, Tomoyuki Fujii. Antitumor effect of a poly (ADP-ribose) polymerase (PARP) inhibitor in endometrial carcinoma cell lines. [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 2402. doi:10.1158/1538-7445.AM2014-2402
Abstract 2403: Imaging of UVB and UVC-induced DNA damage repair in cancer cells in Gelfoam histoculture and minimal cancer in mice
Authors: Uehara Fuminari , Miwa Shinji , Tome Yasunori , Maehara Hiroki , Kanaya Fuminori , Hiroshima Yukihiko , Yano Shuya , Yamamoto Mako , Matsumoto Yasunori , Efimova Elena V. , Hoffman Robert M. 
Published: May 2015

Abstract
We compared the DNA damage repair response of cancer cells after UVB or UVC irradiation. The DNA-damage repair response to UV irradiation was imaged in tumors growing in 3D Gelfoam® histoculture and in superficial tumors grown in mice. UV-induced DNA damage repair was imaged with GFP fused to the DNA damage response (DDR)-related chromatin-binding protein 53BP1 in MiaPaCa-2 human pancreatic cancer cells. 53BP1 forms foci during DNA damage repair. A clonogenic assay initially showed that UVC and UVB inhibited MiaPaCa-2 cell proliferation in a dose-dependent manner, with UVC having more efficacy. Gelfoam® histocultures and confocal imaging enabled 53BP1-GFP nuclear foci to be observed within 1 h after UV irradiation, indicating the onset of DNA damage repair response. Induction of UVB-induced 53BP1-GFP focus formation was observed up to a depth of 120 µm in MiaPaCa-2 cells on Gelfoam®, while UVC induced foci only to a depth of 40 µm. The MiaPaCa-2 cells irradiated by both UVB and UVC light in a skin-flap mouse model had a significant decrease in tumor growth compared to untreated controls. Moreover, UVB-treatment had greater inhibition of tumor growth compared to UVC. Our results demonstrate that both UVB and UVC are useful tools for the treatment of residual cancer, and UVB was more effective than UVC in vivo, possibly due to greater tissue penetration of UVB because of its longer wavelength.
Citation Format: Fuminari Uehara, Shinji Miwa, Yasunori Tome, Hiroki Maehara, Fuminori Kanaya, Yukihiko Hiroshima, Shuya Yano, Mako Yamamoto, Yasunori Matsumoto, Elena V. Efimova, Robert M. Hoffman. Imaging of UVB and UVC-induced DNA damage repair in cancer cells in Gelfoam histoculture and minimal cancer in mice. [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 2403. doi:10.1158/1538-7445.AM2014-2403
Abstract 2409: BCL10 regulates RNF8/RNF168-mediated ubiquitination in the DNA damage response
Authors: Zhao Hongchang , Zhu Min , Xu Xingzhi 
Published: May 2015

Abstract
Our genome is constantly attacked by a variety of endogenous and environmental agents. Timely and properly cellular response to DNA damage is essential for maintenance of genome stability and integrity, which plays key roles in prevention of tumor initiation and development. B-cell lymphoma/leukemia 10 (BCL10), when translocated or mutated, contributes to mucosa-associated lymphoid tissue lymphomas and other malignancies. However, the mechanisms by which the resulting aberrant expression of BCL10 leads to tumorigenesis are poorly understood. In this report, we uncovered that, in response to DNA damage, BCL10 is recruited to the damage sites and modified sequentially by phosphorylation and ubiquitination. Modified BCL10 in turn facilitates to bring about cascades of ubiquitination and recruitment of DNA damage response (DDR) factors, promoting high-fidelity DNA repair. Furthermore, BCL10 is over-expressed in breast tumors (376 cases of breast cancer vs. 62 cases of normal breast, p=0.000). Taken together, our study reveals a novel function of BCL10 in ubiquitination-driven DDR, contributing to the maintenance of genome stability and integrity.
Note: This abstract was not presented at the meeting.
Citation Format: Hongchang Zhao, Min Zhu, Xingzhi Xu. BCL10 regulates RNF8/RNF168-mediated ubiquitination in the DNA damage response. [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 2409. doi:10.1158/1538-7445.AM2014-2409
Abstract 2418: Investigating p53 and other potential determinants of cell sensitivity to ATR inhibition by VE-821
Authors: Middleton Fiona K. , Chen Tao , Pollard John R. , Curtin Nicola J. 
Published: May 2015

Abstract
Background: Defects in the multifactorial DNA damage response (DDR) are common in cancer, making them vulnerable to inhibitors of other components of the DDR. ATR is a key component of the DDR, signalling ssDNA, arising from stalled replication forks, resected double strand breaks (DSBs) and NER intermediates to activate cell cycle arrest at the S/G2 checkpoints and initiate homologous recombination repair (HRR). Tumors often have a dysfunctional G1 checkpoint e.g. due to p53 mutations or other DDR defects. ATR inhibition of the S/G2 checkpoints and HRR has the potential to exploit these defects and selectively target cancer. VE-821 is a potent ATR inhibitor under advanced pre-clinical investigation
Hypotheses: 1) Cells with dysfunctional p53 will be more sensitive to ATR inhibition. 2) Defects in other DDR components will sensitise cells to ATR inhibition.
Methods: The survival of isogenic p53 mutant/null and wt/corrected human cell lines (HCT116 p53+/+ and p53-/- or U2OS p53WT and p53DN (dominant negative)) and a panel of repair defective Chinese hamster ovary and lung fibroblast cells was determined using colony formation after 24 hours exposure VE-821 alone or in the presence of gemcitabine or ionising radiation.
Results: There was no significant difference in sensitivity to VE-821 between p53 wt or mutant/null cells in either HCT116 (LC50 = 2.13 and 4.56 µM, respectively) or U2OS pairs (LC50 = 2.54 and 3.34 µM, respectively). However, 1 µM VE-821 significantly potentiated the antimetabolite, gemcitabine, in HCT116 p53-/- (4.3-fold) but not p53+/+ cells (1.5-fold), and enhanced cell kill by 100 nM gemcitabine 40-fold in U2OS p53DN cells but only 3-fold in U2OS p53WT cells. Chinese hamster ovary cells defective in XRCC1 (single stranded break repair) were more sensitive to single agent VE-821 than the parental wt cells (35% and 55% survival at 10 µM, respectively). Data on other repair-defective cell lines will be presented.
Conclusions: p53 status is not a determinant of sensitivity to VE-821 as a single agent but VE-821 preferentially sensitises cells lacking functional p53 to gemcitabine. This supports the hypothesis that p53 status may be predictive of cellular response to ATR inhibition in combination with certain chemotherapies. Furthermore, data using Chinese hamster cell lines indicate that DDR defects may be exploited by ATR inhibition.
Citation Format: Fiona K. Middleton, Tao Chen, John R. Pollard, Nicola J. Curtin. Investigating p53 and other potential determinants of cell sensitivity to ATR inhibition by VE-821. [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 2418. doi:10.1158/1538-7445.AM2014-2418
Abstract 2424: DNA mismatch repair protein, PMS2, induces apoptosis in human prostate cancer cells
Authors: Fukuhara Shinichiro , Chang Inik , shahryari varahram , gill ankurpreet , wong darryn K. , yamamura soichiro , majid shahana , saini sharanjot , hirata hiroshi , ueno koji , deng gouren , tabatabai laura Z. , nonomura norio , dahiya rajvir , tanaka yuichiro 
Published: May 2015

Abstract
Prostate cancer is one of the most common malignancies and ranks the second most common cause of cancer-related deaths in men. DNA mismatch repair (MMR) enzymes act as proofreading complexes that maintain the genomic integrity and MMR-deficient cells show an increased mutation rate. Recent studies have shown that MMR influences the regulation of tumor development in various cancers such as colon, ovarian and others, but their effect on prostate cancer growth has not been investigated thus far. The aim of the present study was to investigate the effect of the post-meiotic segregation (PMS) 2 MMR gene on growth properties of prostate cancer cells. Expression of PMS2 was initially measured in normal and cancerous prostate cell lines by real-time PCR and western blotting. Cancerous cells displaying the lowest levels compared to normal cells was then transfected with PMS2. Gene effect on various cellular properties (cell proliferation, migration, invasion, apoptosis and cell cycle assays) as well as growth in nude mice were determined. Of the various prostate cell lines, DU145 had dramatically reduced expression levels of PMS2 with little protein detected, whereas levels were high in normal prostate cells. Interestingly, over-expressing the PMS2 gene in DU145 cells decreased cell proliferation, migration and invasion, and increased apoptosis and cell cycle arrest compared to vector control. PMS2 also inhibited DU145 cell tumor formation in animal models. These results demonstrate PMS2 to protect against prostate cancer progression and to have a functional role by affecting apoptosis and cell cycle of prostate cancer cells.
Citation Format: Shinichiro Fukuhara, Inik Chang, varahram shahryari, ankurpreet gill, darryn K. wong, soichiro yamamura, shahana majid, sharanjot saini, hiroshi hirata, koji ueno, gouren deng, laura Z. tabatabai, norio nonomura, rajvir dahiya, yuichiro tanaka. DNA mismatch repair protein, PMS2, induces apoptosis in human prostate 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 2424. doi:10.1158/1538-7445.AM2014-2424
Abstract 2425: Exploiting DNA repair defects in breast cancer
Authors: Naipal Kishan A.T. , Verkaik Nicole S. , Brugge Petra ter , Ameziane Najim , Deurzen Carolien H.M. van , Martens John W. , Winter Johan P. de , Jonkers Jos , Vreeswijk Maaike P. , Jager Agnes , Hoeijmakers Jan , Kanaar Roland , Gent Dik C. van 
Published: May 2015

Abstract
One of the hallmarks of cancer is genetic instability. Many chemotherapeutic strategies make use of DNA damaging agents, that preferentially target dividing cells. Recently, DNA repair defects have been identified in many different types of tumors, suggesting that the effectiveness of such treatments may be modulated by the precise genetic make-up of the tumor; defects in specific DNA repair pathways can be used as the Achilles' Heel of the tumor. An important new concept is synthetic lethality, the observation that combinations of mutations can be lethal, while both single mutations are viable. In selected tumors, the specific DNA repair defect can be targeted in such a way that the tumor cells can be killed without causing severe side effect on normal tissues. The combination of PARP inhibitors and homologous recombination (HR) deficient hereditary breast cancer is on its way to the clinic and more combinations are currently in the preclinical phase. Selection of breast cancer patients for targeted treatment with PARP inhibitors requires a validated test to identify HR deficient tumors. For this purpose, we have assessed ionizing radiation induced RAD51 foci (IRIF) after ex vivo irradiation of individual breast tumor slices as a marker for HR defects. We validated this approach in known HR- deficient tumors, where we found a severe defect in RAD51 IRIF formation. Subsequently, we used this assay to identify a subgroup of HR deficient primary breast cancers. Out of 42 tumors, we found five HR deficient breast cancers, caused by two distinct modes of BRCA gene inactivation, mutations and promoter hypermethylation. HR deficiency was significantly associated with high grade, triple-negative breast cancer (TNBC). A large fraction of TNBC showed HR defects, suggesting that PARP inhibitors may be particularly promising for this group of tumors that currently have a poor prognosis. We conclude that the RAD51 IRIF assay is a powerful tool to select patients with HR-deficient primary breast cancers eligible for PARP-inhibitor treatment in the clinic. These approaches may change cancer medicine in a fundamental way, from a one-size-fits-all concept to an individualized treatment strategy based on the functional molecular make-up of the tumor for each patient.
Citation Format: Kishan A.T. Naipal, Nicole S. Verkaik, Petra ter Brugge, Najim Ameziane, Carolien H.M. van Deurzen, John W. Martens, Johan P. de Winter, Jos Jonkers, Maaike P. Vreeswijk, Agnes Jager, Jan Hoeijmakers, Roland Kanaar, Dik C. van Gent. Exploiting DNA repair defects in breast 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 2425. doi:10.1158/1538-7445.AM2014-2425
Abstract 2429: Temporally and spatially inducible mouse model of aneuploidy
Authors: Eichberg Daniel , Knouse Kristin , Amon Angelika 
Published: May 2015

Abstract
Aneuploidy, the state in which cells have an abnormal number of chromosomes, is a hallmark of most human cancers. Despite aneuploidy's near-ubiquitous presence in tumors, it is unknown whether aneuploidy is a driver or passenger in cancer progression. Aneuploidy is normally prevented by the spindle assembly checkpoint (SAC), a critical cellular mechanism which blocks chromosomal missegregation by inhibiting premature sister chromatid separation during mitosis. Although transgenic mouse models with defective SAC proteins exist, the dysfunctional proteins are expressed constitutively from birth in all tissues, a milieu that differs from that of an in vivo human tumor in which cancer cells develop aneuploidy de novo in the context of a euploid organism. In order to generate a mouse model that more closely approximates this tumor environment, we will insert single copies of shRNA hairpins that target SAC proteins BubR1 or Mad2 into the mouse genome at the Col1A1 locus using recombination mediated cassette exchange. shRNA expression will be under the control of a tetracycline responsive element in tissues that co-express rtTA, leading to temporally and spatially inducible disruption of the SAC, and thus aneuploidy. In vitro shRNA construct validation experiments indicate our shRNAs successfully knockdown target RNA and protein levels, as well as functionally promote mitotic slippage after nocodazole arrest, which is indicative of an impaired SAC. We will use this mouse model to investigate the role of increased chromosomal missegregation on tumor initiation and evolution, as well as the impact of increased aneuploidy on normal organ function.
[Daniel Eichberg is a Howard Hughes Medical Institute Medical Research Fellow.]
Citation Format: Daniel Eichberg, Kristin Knouse, Angelika Amon. Temporally and spatially inducible mouse model of aneuploidy. [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 2429. doi:10.1158/1538-7445.AM2014-2429
Abstract 2431: Downregulation of PHLPP promotes glycolysis in colon cancer cells
Authors: Wen Yang-an , Xiong Xiaopeng , Gao Tianyan 
Published: May 2015

Abstract
PHLPP belongs to a novel family of Ser/Thr protein phosphatases. Our previous studies have shown that PHLPP can antagonize multiple signaling pathways by negatively regulating signaling molecules such as Akt, S6K, and PKC. Functionally, PHLPP serves as a tumor suppressor to inhibit cell proliferation, promote apoptosis and increase therapeutic sensitivity in colon cancer cells. Here, we further examined the role of PHLPP in regulating metabolic pathways in colon cancer. Control and PHLPP knockdown cells colon cancer cells, as well as wild-type and Phlpp knockout MEF cells, were subjected to bioenergetic phenotype analysis using Seahorse XF96 analyzer. The mitochondrial respiration measurements revealed that decreased PHLPP expression resulted in an increase in oxygen consumption rate (OCR) suggesting enhanced cellular respiration. In addition, PHLPP depletion significantly stimulated glycolysis as indicated by increased extracellular acidification rate (ECAR). Consistently, the rates of glucose consumption and lactate production were significantly increased in PHLPP knockdown cells. Furthermore, the numbers of apoptotic cells were increased in PHLPP knockdown cells compared to control cells when cultured in glucose-free medium, suggesting that loss of PHLPP expression render cells more sensitive to glucose deprivation as they became relied on glycolysis. To begin determining the underlying molecular mechanism, we found that the activity of both Akt and S6K was largely induced in PHLPP-knockdown cancer cells and PHLPP-knockout MEF cells. Since both kinases are known to play important roles in re-programming metabolic networks to favor tumor growth, it is likely that PHLPP inhibits glycolysis by negatively regulating Akt- and S6K-mediated metabolic effects. Taken together, our studies identified PHLPP as a novel regulator of glucose metabolism in colon cancer cells. Downregulation of PHLPP may promote tumorigenesis by providing metabolic advantages in colon cancer
Citation Format: Yang-an Wen, Xiaopeng Xiong, Tianyan Gao. Downregulation of PHLPP promotes glycolysis in colon 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 2431. doi:10.1158/1538-7445.AM2014-2431
Abstract 2433: Metabolic reprogramming by an epigenetic mechanism in endocrine therapy resistance of breast cancer
Authors: Zou June X. , Wang Junjian , Duan Zhijian , Chen Hongwu , Kung Hsing-Jien , Chen Xinbin , Murphy Leigh C. , Borowsky Alexander 
Published: May 2015

Abstract
Metabolic reprogramming is a major mechanism of fueling cancer cell growth and proliferation. However, how tumor metabolism is altered to confer therapeutic resistance is poorly understood. Gene expression profiling of tamoxifen sensitive and resistant breast cancer cells revealed that transition to the resistance was associated with a specific expression reprogramming of genes involved in glucose/energy metabolism, which was accompanied by aberration of specific epigenetic regulators such as the histone methyltransferase NSD2/MMSET/WHSC1. In cell and xenograft tumor models, NSD2 overexpression alone was sufficient to confer tamoxifen resistance. Analysis of clinical specimens indicates that NSD2 was a strong predictive factor for early relapse of tamoxifen therapy. NSD2 wild type, but not its methylase-defective mutant form, coordinately stimulated the expression and enzymatic activity of HK2, TIGAR and G6PD and strongly augmented the pentose phosphate pathway (PPP) production of NADPH for ROS reduction and survival of tamoxifen treated cells and tumors. Further mechanistic studies demonstrated that elevated NSD2 stimulates the metabolic gene expression through H3K36 methylation at the target chromatin. Pharmacological targeting aberrant NSD2 by DZNeP, an S-adenosylhomocysteine (AdoHcy) hydrolase inhibitor, effectively blocked the growth of tamoxifen-resistant tumor. The study reveals a novel mechanism of cancer metabolic reprogramming and suggests targeting the key metabolic re-programmer as a viable option for effective treatment of endocrine resistant tumors.
Note: This abstract was not presented at the meeting.
Citation Format: June X. Zou, Junjian Wang, Zhijian Duan, Hongwu Chen, Hsing-Jien Kung, Xinbin Chen, Leigh C. Murphy, Alexander Borowsky. Metabolic reprogramming by an epigenetic mechanism in endocrine therapy resistance of breast 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 2433. doi:10.1158/1538-7445.AM2014-2433