bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3400: Progression of epidermal growth factor receptor (EGFR)-independent colorectal cancer
Authors: Rojas Carolina Mantilla , Ming Yu , Threadgill David 
Published: July 2017

Abstract
When combined with standard of care treatment for colorectal cancer (CRC), the use of monoclonal antibodies or small molecule inhibitors against epidermal growth factor receptor (EGFR) show modest efficacy in the clinic. Early detection efforts and more effective therapies have reduced mortality, yet CRC remains the second mostly deadly cancer in the United States with approximately 50,000 deaths expected this year. Thus, it is imperative to better understand the mechanisms governing molecular progression of CRC. Primary and secondary resistance to anti-EGFR therapies occurs in approximately 80% of the patients with CRC. Mutations in Kras explain some non-responding CRCs, but even in cancers lacking Kras mutations, little is known about which cancers are likely to respond to EGFR targeted treatment, suggesting an alternative and EGFR-independent CRC progression mechanism. In this study, we used a conditional Egfr allele (Egfrf) within the ApcMin/+ mouse model and identified EGFR-independent tumors with faster growth rates than those developing in EGFR-wild type mice. To assess aggressiveness of EGFR-independent tumors, we used a metastatic CRC mouse model containing conditionally inactivated Apc alleles (Apcf/f) in combination with a conditionally active allele of Kras (KrasLSL-G12D). It has been reported that delivery of Cre recombinase-expressing adenovirus to the distal colon of these mice results in tumors that progress to carcinoma within 20 weeks, and liver metastases develop in approximately 20% of mice at 24 weeks. We discovered a 10% increase in the penetrance of tumors arising in the absence of EGFR (Egfrf/f, Apcf/f, KrasLSL-G12D/+). Endoscopic analysis suggests an increase in tumor multiplicity in EGFR-deficient tumors when compared with tumors developing in EGFR-wild-type mice. Biweekly colonoscopies confirmed that colonic tumors have a faster growth rate in the absence of EGFR. High-frequency abdominal ultrasound suggests liver metastasis at 16 weeks in 20% of mice lacking EGFR. These findings demonstrate the existence of an EGFR-independent mechanism by which CRC can arise and progress. Moreover, tumors lacking EGFR grow larger than those developing under normal EGFR activity and may be a more aggressive form of CRC. We also have evidence that ERBB3 and ERBB4, related EGFRs, mediate compensatory and alternative pathways, suggesting an important role for these receptors in the progression of EGFR-independent CRC. This study will advance our understanding of ERBB family biology during colonic tumorigenesis, ultimately contributing to better therapies for CRC.
Citation Format: Carolina Mantilla Rojas, Yu Ming, David Threadgill. Progression of epidermal growth factor receptor (EGFR)-independent colorectal 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 3400. doi:10.1158/1538-7445.AM2017-3400
Abstract 3406: Hereditary risks of male breast cancer in a multi-gene panel testing cohort
Authors: Chao Elizabeth C. , Pritzlaff Mary , Pia Summerour , McFarland Rachel , Li Shuwei , Dolinsky Jill , Goldgar David , Shimelis Hermela , Couch Fergus , Holly LaDuca 
Published: July 2017

Abstract
While the population-based risk for breast cancer in males remains relatively low (1:1000), inherited predisposition can significantly raise this to as high as 10%, in men who carry a mutation in the BRCA2 gene. Lifetime breast cancer risks of 1-2% have also been reported in men who carry a mutation in BRCA1. These risks, as well as elevated risks of prostate, pancreatic, and melanoma cancers, are important to discuss in families diagnosed with Hereditary Breast and Ovarian Cancer Syndrome, which is often viewed as being clinically relevant only to the women in an affected family. However, beyond the BRCA1/2 genes, limited data is available on hereditary predisposition to male breast cancer. We analyzed clinical histories and molecular results from multi-gene panel testing for hereditary cancer predisposition in a cohort of 715 men affected by breast cancer. A total of 708 male breast cancer patients were eligible for inclusion in the final analysis. Molecular testing included analysis of 5 to 59 genes for DNA coding sequence and copy number variants by next-generation sequencing and microarray. Genetic variants identified were classified according to a 5-tier system using previously validated algorithms1,2. Only those variants classified as pathogenic or likely pathogenic were included in the analyses as positive for a mutation. Overall, a mutation was detected in 18% of these men. Four subjects carried a mutation in two different breast cancer predisposition genes. BRCA2 and CHEK2 were the most frequently mutated genes. The risk of breast cancer was significantly elevated compared to public controls in individuals with a mutation in BRCA2 (odds ratio (OR)=13.9; p=1.92x10-16), CHEK2 (OR=3.8; p=6.24x10-24) and PALB2 (OR=6.6, p=0.01). Average age was similar amongst men with (63.5±2.7 years) and without (62.3±1.2 years) mutations, as were clinical and family histories of additional cancers. The high overall diagnostic yield suggests the utility of testing all male breast cancer patient regardless of age or family history by multigene panel testing, and provides data to support risk-based counseling and medical recommendations for screening and/or prevention in male mutation carriers.
1. 1. LaDuca et al. Genet Med. 2014 Nov;16(11):830-7 2. 2. Richards et al. Genet Med. 2015 May;17(5):405-24
Citation Format: Elizabeth C. Chao, Mary Pritzlaff, Summerour Pia, Rachel McFarland, Shuwei Li, Jill Dolinsky, David Goldgar, Hermela Shimelis, Fergus Couch, LaDuca Holly. Hereditary risks of male breast cancer in a multi-gene panel testing cohort [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 3406. doi:10.1158/1538-7445.AM2017-3406
Abstract 3407: Side effects of BRAF inhibitors mimic RASopathies
Authors: Sfecci Alicia , Dupuy Alain , Dinulescu Monica , Droitcourt Catherine , Adamski Henri , Hadj-Rabia Smail , Odent Sylvie , Galibert Marie-Dominique , Boussemart Lise 
Published: July 2017

Abstract
Recent advances in targeted anticancer therapies have substantially improved the prognosis of several cancers but they are not free of side effects. These side effects are, however, clearly distinct from those induced by classical cytotoxic chemotherapies, likely because targeted therapies are designed to interfere with specific oncogenic signaling pathways and not to inhibit cell proliferation in general. We, therefore, evaluated whether specific side effects of BRAF inhibitor therapies would resemble symptoms seen in patients with RASopathies, in which the MAPK pathway is affected and which includes Costello, Noonan and Cardio-Facio-Cutaneous syndromes. To this end, we collected a cohort of 18 patients with genetically confirmed RASopathies that were followed between 2012 and 2016 at the University Hospital of Rennes, France and that were evaluated based on their personal medical history and a clinical examination. Strikingly, RASopathy patients, particularly those with Cardio-Facio-Cutaneous syndrome, showed symptoms resembling those that we and others have previously seen in genetically characterized patients undergoing BRAF inhibitor treatment. These symptoms included keratosis pilaris, wavy hair, sparse eyelashes/eyebrows, poor hair growth, palmo-plantar hyperkeratosis in areas of pressure, verrucous papillomas, nevi efflorescence, and increased cancer risk. Nevertheless, BRAF-inhibitor treatment can also lead to side effects not typically found in patients with RASopathies, including acneiform dermatitis and vemurafenib-specific phototoxicity, which may even increase under a combined BRAF/MEK inhibition. These results suggest that the side effects of BRAF inhibition that are similar to symptoms in patients with RASopathies are due to direct targeting of the MAPK pathway in BRAF-non-mutated (wild type) cells while those that are dissimilar represent off-target effects that do not affect the MAPK pathway. We hope that this type of comparative analysis may lead to a better understanding of the multiple effects of targeted therapies and perhaps prompt modifications in the targeted therapy approach to minimize these side effects.
Citation Format: Alicia Sfecci, Alain Dupuy, Monica Dinulescu, Catherine Droitcourt, Henri Adamski, Smail Hadj-Rabia, Sylvie Odent, Marie-Dominique Galibert, Lise Boussemart. Side effects of BRAF inhibitors mimic RASopathies [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 3407. doi:10.1158/1538-7445.AM2017-3407
Abstract 3419: Uncovering the functional relevance of FBXW7 mutations in endometrial cancer
Authors: Urick Mary Ellen , Hong Bo , Rudd Meghan L. , Bell Daphne W. 
Published: July 2017

Abstract
The goal of this study is to elucidate the functional consequences of FBXW7 mutations in the context of endometrial carcinoma (EC). EC is a heterogeneous disease, consisting of multiple histological subtypes associated with distinct clinical outcomes. Endometrioid endometrial cancer is the most commonly diagnosed subtype and is associated with an overall favorable prognosis. Less common but more clinically aggressive subtypes that contribute disproportionately to patient deaths include clear cell and serous ECs. We previously reported that FBXW7 is somatically mutated in 10% of endometrioid, 13% of clear cell and 29% of serous ECs. FBXW7 functions as a substrate-recognition protein within a SKP/CUL1/F-Box ubiquitin ligase complex, which targets numerous proteins for ubiquitin-mediated proteosomal degradation. Although FBXW7 is a known tumor suppressor, the functional consequences of these mutations have not yet been fully elucidated in the context of EC. As a means to this end, we utilized shRNA and Western blotting to identify proteins that are upregulated following FBXW7 depletion in ARK1 serous EC cells. Among proteins that were consistently upregulated were cyclin E1 and cMYC. We treated EC cells harboring endogenous FBXW7 mutations and those with wildtype FBXW7 with a proteasome inhibitor to confirm that EC cells regulate cyclin E1 and cMYC through proteasome degradation. Furthermore, we identified three EC cell lines that harbor endogenous mutations in FBXW7 and show that these cell lines exhibit delayed degradation of these substrates compared to EC cells expressing wildtype FBXW7. Finally, we generated expression constructs for wildtype FBXW7α and six recurrent mutants found in EC. We show that transient exogenous overexpression of five out of six recurrent FBXW7 mutant constructs in two different serous EC cell lines resulted in increased levels of phosphorylated cMYC and cyclin E1 compared to wildtype FBXW7α. These results suggest that not all recurrent FBXW7 mutations are functionally equivalent. Our findings begin to reveal the molecular consequences of FBXW7 mutations in EC and ongoing studies are aimed at elucidating additional functional consequences of these aberrations in the context of EC.
Citation Format: Mary Ellen Urick, Bo Hong, Meghan L. Rudd, Daphne W. Bell. Uncovering the functional relevance of FBXW7 mutations in endometrial 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 3419. doi:10.1158/1538-7445.AM2017-3419
Abstract 342: WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer
Authors: Saloura Vassiliki , Vougiouklakis Theodore , Zewde Makda , Deng Xiaolan , Kiyotani Kazuma , Park Jae-Hyun , Matsuo Yo , Lingen Mark , Dohmae Naoshi , Suzuki Takehiro , Hamamoto Ryuji , Nakamura Yusuke 
Published: July 2017

Abstract
While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions.
Citation Format: Vassiliki Saloura, Theodore Vougiouklakis, Makda Zewde, Xiaolan Deng, Kazuma Kiyotani, Jae-Hyun Park, Yo Matsuo, Mark Lingen, Naoshi Dohmae, Takehiro Suzuki, Ryuji Hamamoto, Yusuke Nakamura. WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck 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 342. doi:10.1158/1538-7445.AM2017-342
Abstract 3421: Pharmacological inhibition of histone methylation attenuates TGFβ induced EMT characteristics in pancreatic cancer
Authors: Mody Hardik R. , Govindarajan Rajgopal 
Published: July 2017

Abstract
Epithelial-to-Mesenchymal Transition (EMT) is a tumor cell remodeling process that drives progression of several epithelial solid tumors including pancreatic tumors. Transforming growth factor (TGF) β signaling is a key promoter of EMT pathway and remains an attractive target for curtailing tumor progression. Here we present a strategy for investigating inhibitors of TGFβ signaling in pancreatic cancer via reprograming of miRNAs. We find a carbocyclic adenosine analog and histone methyl transferase inhibitor, 3-deazaneplanocin A (DZNep) to significantly attenuate the TGFβ signaling induced EMT characteristics in pancreatic ductal adenocarcinoma (PDAC). Specifically, we find DZNep treatment to restore expression of selective epigenetically silenced miRNAs (mir-663a, miR-4787-5p, and miR-202) that inhibit endogenous TGFβ1 ligand and receptor expression via RNA interference. Consequently, DZNep significantly attenuated both exogenous and endogenous TGFβ-induced EMT response. Lentiviral overexpression of mir-663a, miR-4787-5p or miR-202 reduced tumor cellular proliferation and EMT phenotypic characteristics similar to DZNep in cultured pancreatic cancer cells, whereas locked nucleic acids inhibition of miRNAs abrogated such effects. In an orthotopic pancreatic cancer mouse model, DZNep and all three miRs reduced overall tumor burden in pancreas and metastatic load in liver, lungs and spleen. Together, these findings suggest epigenetic reprograming of miRNAs by synthetic histone methylation reversal agents as a potentially viable approach for attenuating TGFβ signaling pathway involved in pancreatic cancer progression.
Citation Format: Hardik R. Mody, Rajgopal Govindarajan. Pharmacological inhibition of histone methylation attenuates TGFβ induced EMT characteristics in pancreatic 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 3421. doi:10.1158/1538-7445.AM2017-3421
Abstract 3423: Elucidation of the role of miR-575 on tumorigenesis in glioblastoma
Authors: Gray Ashley N. , Cui Tiantian , Geurts Marjolein , Robe Pierre , McElroy Joseph , Bell Erica Hlavin , Chakravarti Arnab 
Published: July 2017

Abstract
Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival rate less than 15 months, with only 3-5% of patients survive more than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. MiRNAs are small regulatory molecules that play a crucial role in carcinogenesis via repression of oncogenes and tumor-suppressor genes either transcriptionally or post-transcriptionally. Our clinical data (n=268) shows that miR-575 is one of the top miRNAs associated with GBM overall survival (FDR: 0.0036, p-value: 5.77E-05) by univariate analysis (NanoString Technologies; Seattle, WA). This study was designed to investigate the expression and function of miR-575 in GBM. Basal expression of miR-575 was first detected in GBM cell lines prior to functional experimentation. Cell proliferation, colony formation, migration and invasion assays were performed to understand the role of miR-575 in GBM. We found that overexpression of miR-575 significantly increased cell proliferation and cell motility in LN229 and U251 cell lines. Additionally, BLID, a tumor-suppressor gene, was negatively regulated by miR-575 at the transcriptional level by qRT-PCR, which will be further investigated at the post-transcriptional level by western blot. Up-regulation of miR-575 in GBM cell lines suggests that it could be acting as an oncogene by degrading the mRNA of BLID. Luciferase assays also showed negative regulation of BLID expression by miR-575, supporting our hypothesis and findings in other cancers. In conclusion, miR-575 might act as an oncogene in GBM, and BLID may be a putative target gene of miR-575. This mechanism could potentially be useful as a novel prognostic biomarker for GBM patients after further in vitro and in vivo validation. Funding: 1R01CA169368 (PI: Houghton; Co-I:Chakravarti); 1R01CA11522358 Multiple-PI R01: Chakravarti (PI); Xia (PI); 1R01CA1145128 Baroukhim (PI); Chakravarti (Co-PI) 7/2015-6/2020; R01CA108633 (PI:Chakravarti); 1RC2CA148190 (Scientific PI: Chakravarti).
Citation Format: Ashley N. Gray, Tiantian Cui, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti. Elucidation of the role of miR-575 on tumorigenesis in glioblastoma [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 3423. doi:10.1158/1538-7445.AM2017-3423
Abstract 3432: microRNA expression reflects site specificity of metastatic colorectal cancer
Authors: Fromm Bastian , Høye Eirik , Domanska Diana , Lund-Andersen Christin , Kristensen Annette Torgrund , Dagenborg Vegar J. , Boettger Paul H. , Abrahamsen Torveig W. , Solberg Steinar , Larsen Stein G. , Edwin Bjørn , Hovig Eivind , Lorenz Susanne , Flatmark Kjersti 
Published: July 2017

Abstract
Colorectal Cancer (CRC) is one of the leading causes of cancer related deaths in the western world, and metastatic progression is the dominating cause of mortality. The primary site of CRC metastasis is the liver, followed by the lungs and peritoneal cavity, and prognosis for patients with metastatic CRC (mCRC) is poor, with only 10 % five-year survival. Although much is known about progression and metastasis of CRC; how primary CRC (pCRC) differs from mCRC on the molecular level and potential differences between metastases located in different organs are incompletely understood. This is important for our understanding of the disease, but also could have significant implications with respect to treatment. MicroRNAs have been shown to be key elements in cancer progression, but recent reports on CRC failed to consistently identify microRNA signatures of metastatic progression. We have addressed this using a smallRNA sequencing approach to analyze primary tumors and a set of liver, lung and peritoneal metastases, including corresponding adjacent tissue (colon, liver, lung, peritoneum). Further, we use the highly curated and updated microRNA reference MirGeneDB.org, the novel pipeline MirAthon - including a correction-algorithm of benign tissue microRNA signatures for tumor or metastatic samples, and we compare pCRC and site specific metastases separately. We are able to show that microRNA profiles of mCRC are distinct to pCRC in a site-specific manner. We identify a small panel of differentially expressed microRNAs including isoforms (isomiRs) hidden under a layer of benign signatures that we confirmed in other available datasets, too. Our findings will help better understand metastatic progression and site-specificity in CRC and could be potential biomarkers for mCRC.
Our work identifies microRNA signatures of mCRC and suggest that microRNA signatures reflect mCRC site specificity. Furthermore, the results underline the importance of using a curated reference for microRNA studies, and to differentiate metastases based on their localization ab initio.
Citation Format: Bastian Fromm, Eirik Høye, Diana Domanska, Christin Lund-Andersen, Annette Torgrund Kristensen, Vegar J. Dagenborg, Paul H. Boettger, Torveig W. Abrahamsen, Steinar Solberg, Stein G. Larsen, Bjørn Edwin, Eivind Hovig, Susanne Lorenz, Kjersti Flatmark. microRNA expression reflects site specificity of metastatic colorectal 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 3432. doi:10.1158/1538-7445.AM2017-3432
Abstract 3433: Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular carcinoma
Authors: Yasui Kohichiroh , Iwai Naoto , Terasaki Kei , Gen Yasuyuki , Itoh Yoshito 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in the development of HCC, a genome-wide miRNA gene expression analysis was performed using the human miRNA microarray (Agilent) in paired HCC tumors and non-tumorous liver tissues from patients with primary HCC. The array-based miRNA expression profiles were validated by quantitative PCR. We also screened for genes with promoter DNA hypermethylation using a genome-wide DNA methylation microarray analysis (the Illumina HumanMethylation27 BeadChip) in the same samples. We found that miR-214-3p were significantly down-regulated by aberrant promoter hypermethylation in HCC tumors compared to the non-tumorous liver tissues. We identified PSMD10, which encodes gankyrin, as a direct target of miR-214-3p using luciferase assay and immunoblotting. Gankyrin, an oncoprotein commonly overexpressed in HCC, binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Our experiments showed that reduced miR-214-3p expression was associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in HCC cells. In conclusion, our results suggest that epigenetic silencing of tumor suppressor miR-214-3p is involved in hepatocarcinogenesis through up-regulation of gankyrin expression.
Citation Format: Kohichiroh Yasui, Naoto Iwai, Kei Terasaki, Yasuyuki Gen, Yoshito Itoh. Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular carcinoma [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 3433. doi:10.1158/1538-7445.AM2017-3433