bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4253: Expression profiling of paired benign and breast cancer lesions in African American women
Authors: Holowatyj Andreana Natalie , Ruterbusch Julie J. , Ali-Fehmi Rouba , Bandyopadhyay Sudeshna , Mehner Christine , Mann Melody Stallings , Dyson Gregory , Radisky Derek , Cote Michele L. 
Published: July 2017

Abstract
Benign breast disease, a known risk factor for subsequent breast cancer, includes a histological spectrum of lesions that can be subdivided based on the overall impression into non-proliferative lesions, proliferative lesions without atypia, and atypical hyperplasia. Yet little is known about the molecular characteristics of benign breast tissue from African American women, who suffer from disproportionately high breast cancer mortality rates. 72 breast samples from African American women were obtained. RNA was extracted from archival formalin-fixed, paraffin-embedded (FFPE) blocks. Gene expression profiling was performed on these samples using the Affymetrix HTA2.0 exon array chip. A fit linear model using generalized least squares identified probe sets with differential expression in benign-in situ and benign-invasive breast cancer paired lesions. 36 benign and 36 breast cancer paired lesions were included in the study. In the benign-in situ set (n=20), 978 probe sets were differentially expressed (threshold: fold-change, 1.50; p &lt; 0.05). Probe sets mapped to 125 annotated genes, of which 69 (55.2%) were involved in cancer. The benign-invasive set (n=52) identified 351 differentially expressed probe sets that mapped to 84 annotated genes, of which 61 (72.6%) had known cancer significance. Genes involved in cellular growth and proliferation were significantly over-expressed in both benign-in situ and benign-invasive lesions (p-values &lt; 0.0104). In the population of 36 paired samples, differentially expressed genes were found to regulate the estrogen receptor (ESR1) through distinct network associations. Many genes are differentially expressed by benign and breast cancer lesions, and in situ/invasive histology contribute to the distinct molecular characteristics and pathways of breast malignancy. Our findings highlight the first study to assess expression profiling of paired benign and breast cancer lesions among African American women.
Citation Format: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote. Expression profiling of paired benign and breast cancer lesions in African American women [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 4253. doi:10.1158/1538-7445.AM2017-4253
Abstract 4256: Impact of diesel engine exhaust exposure on the airway transcriptome
Authors: Drizik Eduard I. , Corbett Sean , Vermeulen Roel , Dai Yufei , Hu Wei , Lenburg Marc , Ren Dianzhi , Duan Huawei , Niu Yong , Xu Jun , Fu Wei , Meliefste Kees , Zhou Baosen , Yang JuFang , Ye Meng , Jia Xiaowei , Meng Tao , Bin Ping , Zheng Yuxin , Silverman Debra , Rothman Nathaniel , Spira Avrum , Lan Qing 
Published: July 2017

Abstract
Rationale: Recent epidemiological studies show that Diesel Engine Exhaust (DEE) exposure is associated with lung cancer, however the mechanism by which this occurs is not well understood. The goal of this study was to assess the transcriptomic alterations in the nasal epithelium of DEE exposed workers from factories where diesel engines are utilized.
Methods: Nasal epithelium brushings were obtained from 41 subjects who work in a factory with DEE exposure, and 38 comparable control subjects who work in factories without any DEE exposure. The median Elemental Carbon (EC) levels of exposed individuals was 60.7μg/m3, with a range of 17.2-105.4 μg/m3, respectively. RNA was isolated from nasal epithelial cells, and profiled for gene expression using Affymetrix microarrays. Linear modeling was used to detect differential expression between DEE exposure and controls. Pathway enrichment in differentially expressed genes was assessed using GO Biological Process and KEGG terms via EnrichR.
Results: We found 234 genes that were differentially expressed between samples derived from DEE exposed participants versus controls at FDR q &lt; 0.25. Within this set of genes, we observed a higher expression of genes involved in oxidative stress response, as well as cell proliferation, cellular transcription, and regulation of apoptosis. In addition, we found that genes involved in ion transport, such as CFTR, were expressed at lower levels in DEE exposed samples.
Conclusions: Chronic DEE exposure associates with changes in the airway transcriptome, with increased stress response as a major effect of DEE exposure. The transcriptomic alterations we identified may help provide insight into the underlying mechanisms of DEE carcinogenicity.
Citation Format: Eduard I. Drizik, Sean Corbett, Roel Vermeulen, Yufei Dai, Wei Hu, Marc Lenburg, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, JuFang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Yuxin Zheng, Debra Silverman, Nathaniel Rothman, Avrum Spira, Qing Lan. Impact of diesel engine exhaust exposure on the airway transcriptome [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 4256. doi:10.1158/1538-7445.AM2017-4256
Abstract 4260: Increased mutation burden in normal-appearing lung tissues with high cancer risk
Authors: Kubo Emi , Takeshima Hideyuki , Motoi Noriko , Ushijima Toshikazu 
Published: July 2017

Abstract
Background:
Genetic alterations are considered to be accumulated in normal tissues at extremely low levels by exposure to various carcinogenic factors, and the degree of accumulated alterations, namely mutation burden, is likely to be associated with cancer risk. In lung tissues, smoking is a well-known carcinogenic factor, and is considered to be involved in accumulation of mutation burden. However, due to the limitation of detection methods of such extremely low frequency mutations, the presence of mutation burden in normal human lung tissues has been unclear. To overcome this limitation, we recently developed a new method to detect mutations with extremely low frequency by sequencing 100 DNA molecules using a next generation sequencer[Yamashita, submitted].
Aim:
We aimed to reveal 1) the presence of mutation burden in normal lung tissues, and 2) its association with cancer risk.
Methods and results:
The presence of somatic mutations was analyzed in 55 cancer-related genes (totally 15,724 bp) in normal lung tissues (n = 11) obtained from background tissues of lung metastasis of cancer patients, without smoking history, other than those with lung cancers (''entirely normal lung tissues'') and non-cancerous lung tissues (n = 11) of lung cancer patients with smoking history (''smoking-exposed normal tissues'').
The mutation frequency in smoking-exposed normal tissues (2.7 ± 0.8×10-5/bases) was significantly higher than that in entirely normal tissues (1.8 ± 0.5×10-5/bases) (p= 0.0189). C to T transition was most frequent in both smoking-exposed normal tissues (60% of detected base substitutions) and entirely normal tissues (61%), but the fractions were not different between the two groups. In contrast, C to A transversion, the signature mutation of smoking, was more frequent in smoking-exposed normal tissues (4%) than in entirely normal tissues (2%). Accumulation of somatic mutations tended to be associated with cancer risk [OR = 3.75 (95% CI = 0.54-26.046)].
Conclusion:
It was shown, for the first time, that somatic mutations were accumulated in normal lung tissues with high cancer risk, possibly by exposure to tobacco smoking.
Citation Format: Emi Kubo, Hideyuki Takeshima, Noriko Motoi, Toshikazu Ushijima. Increased mutation burden in normal-appearing lung tissues with high cancer risk [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 4260. doi:10.1158/1538-7445.AM2017-4260
Abstract 429: Integrated genomic DNA and RNA profiling to predict cancer immunotherapy response
Authors: Du Pan , Wang Xiaohong , Zhao Zhixin , Wang Huiquang , Jia Shidong 
Published: July 2017

Abstract
Immunotherapy response varies widely, making it difficult for physicians to know whether immunotherapy will be effective for a given patient. Recent studies have reported that patients with high PD-L1 gene expression are likely to respond to checkpoint blocking drugs, but there are still many patients whose tumor test for the PD-L1 protein are negative and can respond to the drugs. In addition to the potential link between mismatch repair (MMR) gene mutations and clinical response to anti-PD1 immunotherapy drug, recent findings show that tumor mutation burden and microsatellite instable (MSI) are good indicators of the cancer immunotherapy responses. Using Predicine’s proprietary Gene RADAR (RNA and DNA single molecular digital Readings) technology, here we report the development of PrediSeq-CI (Cancer Immunotherapy) panel for comprehensive genomic profiling of DNA and RNA that are associated with cancer immunotherapy response. The panel has been tested using both tissue biopsy and plasma samples. The development of PrediSeq-CI test has potential to enable precision medicine in cancer immunotherapy. Finally, we also developed a liquid biopsy droplet digital PCR test to measure PD-L1 expression in blood.
Citation Format: Pan Du, Xiaohong Wang, Zhixin Zhao, Huiquang Wang, Shidong Jia. Integrated genomic DNA and RNA profiling to predict cancer immunotherapy response [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 429. doi:10.1158/1538-7445.AM2017-429
Abstract 4293: Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma cells
Authors: Blankstein Anna R. , Ma Shumei , Gibson Spencer B. 
Published: July 2017

Abstract
Ferroptosis, a morphologically and biochemically distinct cell death pathway, is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells. This cell death was blocked by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The objective of the present study was to determine whether lysosome disruptors and tyrosine kinase inhibitors, in combination, induced synergic cell death via the ferroptotic pathway in additional types of cancer. U87 (glioblastoma) and A549 (lung adenocarcinoma) cells were treated with various lysosome disruptors (siramesine or desipramine) in combination with tyrosine kinase inhibitors (lapatinib or sorafenib), and the amount of cell death was measured by trypan blue exclusion. We found that these combinations synergistically induced cell death in U87 and A549 cells. To determine whether ferroptosis was the mechanism of cell death, cells were pretreated with either Fer-1 or DFO (inhibitors of ferroptosis), or with exogenous iron chloride (an inducer of ferroptosis) before treatment with the combination of siramesine and lapatinib. Pretreatment with Fer-1 or DFO decreased cell death by approximately 35%. Pretreatment with iron chloride increased the effect of the drug combination by approximately 45%. Prussian Blue staining demonstrated that there was an increase in intracellular iron accumulation following treatment with the combination of siramesine and lapatinib. Collectively, these data show that in U87 and A549 cells, the combination of lysosome disruptors and tyrosine kinase inhibitors, specifically siramesine and lapatinib, induces ferroptotic cell death. Therefore, inducing ferroptosis in tumor cells is a potential strategy for therapy in these cancers with limited treatment options.
Citation Format: Anna R. Blankstein, Shumei Ma, Spencer B. Gibson. Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma 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 4293. doi:10.1158/1538-7445.AM2017-4293
Abstract 430: Combination of CB-839 and everolimus is effective in inhibiting growth of endocrine resistant breast cancer in vivo
Authors: Fallah Yassi , Demas Diane M. , Demo Susan , Shajahan-Haq Ayesha N. 
Published: July 2017

Abstract
About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Anti-hormone therapy such as antiestrogens are often used to treat ER+ breast cancer but breast cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ~50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. We have shown that endocrine resistant breast cancer cells show an increased dependence on the amino acid glutamine and this process is regulated by MYC activation via the unfolded protein response (UPR). Metabolites of glutamine such as glutamate and proline are significantly elevated in endocrine resistant cells. Cellular changes in glutamine are sensed by the mammalian target of rapamycin (mTOR) complex, mTORC1, which is known to be deregulated in endocrine resistant breast cancer. In this study, we used human antiestrogen (Fulvestrant/Faslodex or Tamoxifen) sensitive and resistant ER+ breast cancer cells and xenografts to test the efficacy of CB-839, an anti-glutaminase, and everolimus (Afinitor), a mTORC1 inhibitor. Combination of CB-839 and everolimus, but not each drug alone, inhibited growth of antiestrogen resistant tumors compared to vehicle alone at 4 weeks post-treatment. The combination treatment did not significantly inhibit growth of antiestrogen sensitive tumors compared with its respective vehicle alone treatment. Thus, a combination strategy that targets glutamine dependence and increased mTOR activation may be a novel strategy in treating endocrine resistant breast cancer.
Citation Format: Yassi Fallah, Diane M. Demas, Susan Demo, Ayesha N. Shajahan-Haq. Combination of CB-839 and everolimus is effective in inhibiting growth of endocrine resistant breast cancer in vivo [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 430. doi:10.1158/1538-7445.AM2017-430
Abstract 4303: Vopp1 physically interacts with Wwox and inhibits its apoptotic function in breast cancer
Authors: Lallemand François , Bonin Florian , Lidereau Rosette , Driouch Keltouma 
Published: July 2017

Abstract
WWOX is a tumor suppressor gene spanning the fragile site FRA16D and targeted by loss of heterozygosity or homozygous deletion in several tumor types. Wwox protein consists of two N-terminal WW domains that mediate protein-protein interactions and a C-terminal short-chain Dehydrogenase/Reductase domain (SDR). The WW1 module acts as a versatile platform linking WWOX with numerous multiprotein complexes. Thus, Wwox suppressor activity relies on its binding capacities to various partners. Wwox has been shown to interact with known proto-oncogenes such as p73, deltaNp63, AP2γ, c-jun, Erbb4, c-Met, Runx2 and Dvl-2. At the cellular level, Wwox has been shown to be a pro-apoptotic protein that induces cell death by acting in both the nucleus and cytoplasm. More recently, emerging evidence also suggest an important role of WWOX in DNA damage response. By using a yeast two-hybrid system and co-immunoprecipitation assays, we characterized Vopp1 (Vesicular Over-expressed in cancer Pro-survival Protein 1) as a new molecular partner of the tumor suppressor Wwox. VOPP1 gene localizes at the frequently amplified 7p11.2 locus and is often co-amplified with EGFR. It is overexpressed in multiple malignancies such as glioblastoma, gastric, head and neck and lung cancers. In this study, we demonstrate that VOPP1 physically interacts with Wwox in breast cancer cells. Upon binding, Wwox is recruited to the Vopp1-containing lysosomal compartment. This recruitment inhibits Wwox-mediated apoptosis at least in part by preventing Wwox-p73 interaction. In addition, Vopp1 acts as an oncogene as shown by its capacity to potentiate cellular transformation. Moreover, in breast cancer clinical samples, VOPP1 overexpression was detected predominantly in tumors retaining Wwox expression. Vopp1 overexpression is associated to a reduced survival of breast cancer patients, especially patients with luminal B tumor types. Remarkably, the VOPP1/WWOX expression ratio showed a significantly worst prognosis outperforming either gene alone. These findings highlight the importance of Wwox compartimentation in addition to Wwox loss in human cancer pathogenesis and define Vopp1 as a novel negative regulator of Wwox whose overexpression induces breast carcinogenesis by affecting the tumor suppressive activity of Wwox.
Citation Format: François Lallemand, Florian Bonin, Rosette Lidereau, Keltouma Driouch. Vopp1 physically interacts with Wwox and inhibits its apoptotic function in breast 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 4303. doi:10.1158/1538-7445.AM2017-4303
Abstract 4304: Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis
Authors: Moriizumi Hisashi 
Published: July 2017

Abstract
Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis Moriizumi Hisashi, Takanori Nakamura and Mutsuhiro Takekawa Div. of Cell Signaling and Mol. Med., IMS, Tokyo Univ. The mitogen-activated protein (MAP) kinase pathway is an important system for cellular responses to extracellular stimuli. Each of the MAPK pathways is composed of MAPKKK, MAPKK and MAPK. In mammalian cells, at least three subfamilies of MAPKs, namely ERK, p38 and JNK, are present. The ERK pathway is activated in response to mitogenic stimuli and plays a key role in proliferation and differentiation. In contrast, the p38 and JNK pathways [collectively called stress-activated protein kinase (SAPK) pathways] regulate cellular stress responses such as apoptosis and cell cycle arrest. MKK4 is unique among the members of the mammalian SAPKK family (i.e., MKK3/4/6/7) in its ability to phosphorylate and activate both p38 and JNK. Interestingly, inactivating mutations of the MKK4 gene are frequently found in many types of cancer. Although MKK4 has been suggested as a tumor suppressor, the molecular mechanism by which MKK4 inhibits tumorigenesis remains unclear. Here we demonstrate that MKK4 can be phosphorylated at specific serine and/or threonine residues by downstream MAPKs(named the “feedback-phosphorylation”)and thereby regulates stress-induced apoptotic cell death. By generating antibodies specific to these phosphorylation sites, we found that under stress conditions both Thr and Ser residues of MKK4 were phosphorylated by JNK, while only the Ser residue was phosphorylated by ERK in response to mitogenic stimuli. In order to clarify physiological significance of the feedback-phosphorylation, we then generated a phosphorylation-deficient mutant of MKK4 (MKK4-AA) by substituting both Thr and Ser residues with Ala. Although the feedback-phosphorylation did not affect the enzymatic activity, stability and subcellular localization of MKK4, we found that cells expressing MKK4-AA mutant suppressed apoptosis induced by various stresses stimuli such as UV irradiation and anticancer drug treatment. These results suggest that feedback-phosphorylation of MKK4 regulates stress-induced apoptosis. Moreover, we are currently investigating the mechanism of how MKK4 affects apoptotic cell death in response to feedback-phosphorylation.
Citation Format: Hisashi Moriizumi. Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis [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 4304. doi:10.1158/1538-7445.AM2017-4304
Abstract 4308: Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human lung adenocarcinoma cells
Authors: Jo Eunbi , Jang Hyun Jin , Jang Ik-Soon 
Published: July 2017

Abstract
Forkhead transcription factor (Foxo3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the caveolin-1 (CAV1)-mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK), and, subsequently Foxo3a translocation into the nucleus, resulting in the upregulation of Bax protein expression. Furthermore, we found that CAV1 overexpression upregulated p-JNK whereas CAV1 siRNA downregulated p-JNK. Additionally, SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation, which attenuated Foxo3a translocation into the nucleus, indicating that CAV1 mediates JNK regulation of Foxo3a. Foxo3a siRNA downregulated Bax protein and attenuated A549 apoptosis, indicating that the CAV1-mediated JNK/Foxo3a pathway induces the apoptosis of A549 lung cancer cells. Cordycepin significantly decreased tumor volume in nude mice. Taken together, these results indicate that cordycepin promotes CAV1 upregulation to enhance JNK/Foxo3a signaling pathway activation inducing apoptosis in lung cancer cells and support its potential as a therapeutic agent for lung cancer.
Citation Format: Eunbi Jo, Hyun Jin Jang, Ik-Soon Jang. Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human lung adenocarcinoma 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 4308. doi:10.1158/1538-7445.AM2017-4308