bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-42: In vivo screen for novel breast cancer promoting genes.
Authors: Huo Yongliang , Macara Ian 
Published: August 2014

Abstract
Mis-regulation of oncogenes and tumor suppressor genes causes cancer. Although the evolution of cancer is not conclusive, most evidence supports that tumors arise from collaboration of multiple genes. To better understand the process of breast tumor initiation and cancer progression we carried out an in vivo screen, for genes that promote tumor formation. Our screen was performed using lentiviral transduction of primary murine mammary epithelial cells, and orthotopic implantation into syngeneic recipient mice. Wild type mammary stem cells can regenerate an entire mammary ductal tree in the recipients. We chose a well-characterized ErbB2/Her2 over-expression mouse model as a source of donor cells because HER2 over-expression occurs in &gt;20% of human breast cancer patients. A cDNA library consisting of a “druggable” set of ~1000 genes was screened in 12 subsets segregated by ORF length. Ten months after transplantation the recipient mice were euthanized and DNA from mammary gland tumors was harvested. No tumors formed in mice transplanted with cells into which a control virus had been transduced. Genes from the library that were expressed in the tumors were identified by sequencing. The ability of these genes to drive tumor formation was confirmed by transduction and transplantation into a second cohort of mice. One of the genes identified in this screen is GTF2I repeat domain containing 1 (GTF2IRD1). Multi-focal atypical hyperplasia formed in mammary glands over-expressing GTF2IRD1 while no hyperplasia was seen in the control mice. This effect depends on the expression of ErbB2 because expression of GTF2IRD1 itself in wild type mammary glands did not cause abnormal growth before the end point. Analysis of the cancer genome atlas database demonstrates that GTF2IRD1 expression is significantly increased in invasive breast cancer compared to normal controls. Therefore, our screen has identified a novel tumor-promoting gene that is of potential clinical importance. A major advantage of our method is the use of normal cells of origin and immunocompetent mice. Moreover, it could be expanded to genome-wide searches for new tumor- and metastasis-promoting genes.
Citation Format: Yongliang Huo, Ian Macara. In vivo screen for novel breast cancer promoting genes. [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-42. doi:10.1158/1538-7445.AM2013-LB-42
Abstract LB-57: Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability.
Authors: Wen Weihong , Peng Cong , Bode Ann M. , Dong Zigang 
Published: August 2014

Abstract
RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1. RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here, we show that knockdown of RNF2 significantly inhibits both cell proliferation and colony formation in soft agar, and induces apoptosis in cancer cells. Knockdown of RNF2 in HCT116 p53+/+ cells resulted in significantly more apoptosis than was observed in RNF2 knockdown HCT116 p53−/- cells, indicating that RNF2 knockdown-induced apoptosis is partially dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 knockdown cells, the p53 protein level was increased, the half-life of p53 was prolonged and p53 ubiquitination was decreased. In contrast, cells overexpressing RNF2 showed a decreased p53 protein level, a shorter p53 half-life and increased p53 ubiquitination. Importantly, we found that RNF2 directly binds with both p53 and MDM2 and promotes MDM2-mediated p53 ubiquitination. RNF2 overexpression could also increase the half-life of MDM2 and inhibit its ubiquitination. The regulation on p53 and MDM2 stability by RNF2 was also observed during the etoposide-induced DNA damage response. These results provide a possible mechanism explaining the oncogenic function of RNF2, and because RNF2 is important for cancer cell survival and proliferation, it might be an ideal target for cancer therapy or prevention.
Citation Format: Weihong Wen, Cong Peng, Ann M. Bode, Zigang Dong. Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. [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-57. doi:10.1158/1538-7445.AM2013-LB-57
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-60: The BRAF:MEK complex reveals new therapeutic strategies for targeting KRASMT tumors.
Authors: Haling Jacob R. , Sudhamsu Jawahar , Hatzivassiliou Georgia , Song Kyung , Belvin Marcia , Hymowitz Sarah , Malek Shiva 
Published: August 2014

Abstract
Spatial activation and regulation of MAPK signaling is determined by genetic context. In BRAFV600E tumor models kinase activity of BRAF is insensitive to normal regulatory mechanisms, whereas in KRASMT tumor models CRAF is the primary driver of the pathway and its function is governed by RAF dimerization, translocation to the plasma membrane, and phosphorylation. Since MEK is a common downstream substrate, multiple allosteric MEK inhibitors are being tested in clinical trials in BRAFV600E and KRASMT cancer types. To date, the efficacy of MEK inhibitors has been substantially higher in BRAFV600E tumors than in KRASMT tumors suggesting that the mechanism regulating MEK activity is different in these settings. In this work, we have discovered that BRAF has a suppressive function in KRASMT tumor lines by forming a stable cytosolic complex with MEK which prevents MEK from being phosphorylated by CRAF. Enrichment of this complex in KRASMT cells results in dampened phospho-MEK levels compared to BRAFV600E cells where little cytosolic BRAF:MEK complexes are observed. Treatment of KRASMT tumor cells with particular classes of MEK inhibitors stabilize the BRAF:MEK complex and inhibit phosphorylation of MEK, while other MEK inhibitors dissociate the complex and enhance MEK phosphorylation. Further we find that the former class of MEK inhibitors selectively prefers binding to the BRAF:MEK complex compared to MEK alone based on the significantly slower off-rate for the BRAF:MEK complex. The crystal structure of a heterotetrameric BRAF:MEK complex in the presence of G-573, an allosteric MEK inhibitor, provides structural rationale for this observation and sheds light on the ability of G-573 and similar classes of MEK inhibitors to prevent RAF phosphorylation of MEK at Ser-218 and Ser-222. Although all MEK inhibitors function to inhibit ERK phosphorylation, our data explains the discrepancy of MEK activation between different classes of MEK inhibitors. Hence we conclude that more effective strategies to treat KRASMT tumors may require targeting signaling protein complexes such as BRAF:MEK as opposed to inhibiting individual components of the pathway. Importantly our work illustrates small molecule kinase inhibitors may not only affect enzymatic activity but also regulate protein-protein interactions thereby influencing pathway signaling.
Citation Format: Jacob R. Haling, Jawahar Sudhamsu, Georgia Hatzivassiliou, Kyung Song, Marcia Belvin, Sarah Hymowitz, Shiva Malek. The BRAF:MEK complex reveals new therapeutic strategies for targeting KRASMT 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-60. doi:10.1158/1538-7445.AM2013-LB-60
Abstract LB-88: A new rapid diagnostic test to identify epidermal growth factor receptor mutations in non-small cell lung cancer.
Authors: Chikumi Hiroki , Takata Miyako , Matsunami Keiji , Matsumoto Shingo , Kotani Masahiro , Sakamoto Tomohiro , Touge Hirokazu , Yamaguchi Kosuke , Kurai Jun , Miyake Naomi , Nakamoto Masaki , Igishi Tadashi , Shimizu Eiji 
Published: August 2014

Abstract
An epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Polymerase chain reaction (PCR)-based methods combined with the use of fluorescence probes, such as the Scorpion Amplification Refractory Mutation System (ARMS) or the PCR-Invader method, are frequently used to detect EGFR mutations before therapy. The sensitivities and specificities of these methods are satisfactory; however, there is potential to further improve the cost and detection time. We developed a new method for the rapid and reliable detection of EGFR mutations by using a combination of mutation-specific primers and the newly developed ultra-rapid real-time PCR (Hyper-PCR) amplification method that can be accomplished in &lt;7 min. We designed specific ARMS primers for the common EGFR del E746-A750 mutations, and optimized the reaction conditions for the PCR machine that contained a thin disc-type reaction vessel, the temperature of which could be quickly altered by rotating it on thermal sources. We used Hyper-PCR to analyze the common EGFR mutations del E746-A750 and L858R in lung cancer samples from 143 non-small cell lung cancer (NSCLC) patients. The results were compared with those obtained by direct sequencing, conventional PCR, and the PCR-Invader method. Using the direct sequencing method, 13 (9.1%) and 15 (10.5%) NSCLC samples were positive for the del E746-A750 and L858R mutations, respectively, while the Hyper-PCR method revealed that 15 (10.5%) and 18 (12.6%) samples were positive for the del E746-A750 and L858R mutations, respectively. Five samples, whose results were discordant between the Hyper-PCR and direct sequencing methods, were analyzed by conventional PCR and the PCR-Invader method, and the results were found to be consistent with those obtained by Hyper-PCR. These results suggest that the novel Hyper-PCR method is an inexpensive, rapid, and reliable diagnostic test for EGFR mutations.
Citation Format: Hiroki Chikumi, Miyako Takata, Keiji Matsunami, Shingo Matsumoto, Masahiro Kotani, Tomohiro Sakamoto, Hirokazu Touge, Kosuke Yamaguchi, Jun Kurai, Naomi Miyake, Masaki Nakamoto, Tadashi Igishi, Eiji Shimizu. A new rapid diagnostic test to identify epidermal growth factor receptor mutations in non-small cell lung 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-88. doi:10.1158/1538-7445.AM2013-LB-88
Abstract LB-99: The novel IGF-IR/Akt-dependent anticancer activities of glucosamine are affected by PIK3CA hot-spot mutations and PTEN deletion.
Authors: Kang Ju-Hee , Song Ki-Hoon , Nam Jeong-Seok , Min Hye-Young , Lee Ho-Young , Cho Sung-Dae , Kim Soo-Youl , Oh Seung Hyun 
Published: August 2014

Abstract
Background: Recent studies have shown that glucosamine inhibits the proliferation of various human cancer cell lines and downregulates the activity of COX-2, HIF-1α, p70S6K, and transglutaminase 2.
Objective: Because the IGF-1R/Akt pathway is a common upstream regulator of p70S6K, HIF-1α, and COX-2, we hypothesized that glucosamine inhibits cancer cell proliferation through this pathway.
Methods: Cell viability was assayed by MTT assay. Total RNA was isolated and reverse transcribed to cDNA for real-time PCR quantification of genes. Western blotting as performed for analyzing expression of proteins. Flow cytometry was performed for apoptosis and cell progression. Balbc/nu mice used in the study for validating results in vivo.
Results: We found that glucosamine inhibited the growth of human non-small cell lung cancer cells in vitro and in vivo and negatively regulated the expression of IGF-1R and phosphorylation of Akt. In other types of cancer cells, including head and neck, breast, prostate, and colon carcinoma cell lines, glucosamine-sensitive cell lines exhibited a more significant decrease in IGF-1R and pAkt levels than glucosamine-resistant cell lines. Interestingly, most of the glucosamine-resistant cell lines have “hot-spot” mutations in PIK3CA, the p110α subunit of PI3K, or loss of PTEN, a negative regulator of Akt activation. In contrast, most of the glucosamine-sensitive cell lines have normal PIK3CA and PTEN genes. Glucosamine decreased the pAkt level through activation of IGF-1R more efficiently in the glucosamine-sensitive than in the glucosamine-resistant cell lines. Furthermore, co-treatment of cells with glucosamine and LY294002, a specific inhibitor of PI3K, significantly enhanced the anticancer effect of glucosamine in the glucosamine-resistant cell lines, whereas transient inhibition of PTEN by siRNA partially decreased the glucosamine sensitivity in the resistant and sensitive cell lines.
Conclusions: Our results indicate that glucosamine is an effective inhibitor of the IGF-1R/Akt pathway and that glucosamine sensitivity of each cell line was affected by the mutation status of PIK3CA and PTEN.
Citation Format: Ju-Hee Kang, Ki-Hoon Song, Jeong-Seok Nam, Hye-Young Min, Ho-Young Lee, Sung-Dae Cho, Soo-Youl Kim, Seung Hyun Oh. The novel IGF-IR/Akt-dependent anticancer activities of glucosamine are affected by PIK3CA hot-spot mutations and PTEN deletion. [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-99. doi:10.1158/1538-7445.AM2013-LB-99
Abstract PL02-01: Cancer genetic and epigenetic interactions.
Authors: Laird Peter W. 
Published: August 2014

Abstract
Cancer develops not only as a result of genetic mutations and genomic rearrangements, but also as a consequence of numerous epigenetic alterations, including extensive changes in the distribution of DNA methylation throughout the genome. DNA methylation changes contribute directly to cancer by transcriptional silencing of tumor-suppressor genes through promoter CpG island hypermethylation.
Cancer genome studies have uncovered somatic mutations in dozens of epigenetic regulators in almost all types of cancer, and integrative analyses have revealed associations between various somatic genetic alterations and broad epigenomic profiles. Some somatic mutations are very tightly associated with distinct epigenetic subtypes, such as CpG Island Methylator Phenotypes (CIMP). In some cases, the somatic mutation appears to contribute causally to the epigenomic profile, such as in the case of mutation of IDH1 in G-CIMP glioblastoma, while in other cases the epigenomic alterations appear to be a prerequisite for somatic mutation, such as colorectal CIMP-associated changes contributing to suppression of mutant BRAF-mediated senescence.
Other cancer epigenomic profiles are attributable to stochastic events or cell-of-origin chromatin states. For example, genomic loci targeted by Polycomb Group Repressors in embryonic stem cells, and involved in cellular differentiation are predisposed to aberrant DNA methylation in cancer cells, suggesting that an epigenetic block to cellular differentiation may sometimes be an initiating event in carcinogenesis. The analysis of whole methylomes at single-basepair resolution reveals that cancer-associated changes occur differentially across defined regions of the genome associated with the nuclear lamina.
It is apparent that epigenomic analysis is essential for a full understanding of the relationship between alterations in the cancer genome and the origin and clinical diversity of individual tumors.
Citation Format: Peter W. Laird. Cancer genetic and epigenetic interactions. [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 PL02-01. doi:10.1158/1538-7445.AM2013-PL02-01
Abstract SY01-01: Regulation of growth by the mTOR pathway.
Authors: Sabatini David M. 
Published: August 2014

Abstract
mTOR is the target of the immunosuppressive drug rapamycin and the central component of a nutrient-and hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has an important role in the control of metabolism and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. I will discuss new results from our lab on the regulation and functions of the mTORC1 and mTORC2 pathways.
Citation Format: David M. Sabatini. Regulation of growth by the mTOR pathway. [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 SY01-01. doi:10.1158/1538-7445.AM2013-SY01-01
Abstract SY05-02: Understanding colorectal cancer as a stem cell hierarchy.
Authors: Batlle Eduard 
Published: August 2014

Abstract
The inner layer of the intestinal tube, the intestinal epithelium, is in a constant process of renewal. Hundreds of millions of terminally differentiated intestinal cells are replaced by new cells every day during the life of an adult organism. This tremendous regenerative power is ultimately sustained by a small population of intestinal stem cells. It is believed that alterations in the biology of human colon stem cells (CoSCs) account for the pathophysiology of various large-bowel disorders, including colorectal cancer (CRC). Yet, the identification of human CoSCs remains elusive. We have recently achieved for the first time the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of the receptor EPHB2 allows the purification of different cell types from human normal colon mucosa biopsies. Colon epithelial cells with highest EPHB2 levels exhibit the longest telomeres and express markers characteristic of intestinal stem cells. Using culturing conditions that recreate the intestinal stem cell niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population. Furthermore, we have also discovered that most human CRCs are constituted by cell populations with phenotypes similar to either CoSCs or intestinal differentiated cells organized into well-defined compartments. CoSC-like cells purified from primary CRCs generate tumors in immunodeficient mice with high efficiency and display both self-renewal and differentiation capacity. We demonstrated that CRC shares a common hierarchy with the intestinal mucosa and that the acquisition of an intestinal stem cell gene program is a central process during disease relapse after therapeutic intervention. Here I will present our latest data on the mechanisms employed by CRC stem cells to regenerate a new tumor at the metastatic site. We have discovered that metastasis relies on a tumor cell non-autonomous program expressed in the microenvironment. This stromal program confers a survival advantage to the disseminated CRC stem cells during the initial phase of metastasis.
Citation Format: Eduard Batlle. Understanding colorectal cancer as a stem cell hierarchy. [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 SY05-02. doi:10.1158/1538-7445.AM2013-SY05-02
Abstract SY12-02: Computational cancer genomics: Biological discovery and translation.
Authors: Schultz Nikolaus , Sander Chris 
Published: August 2014

Abstract
The analysis of genes and cellular pathways that are altered in different cancers can lead to biological discoveries and potential patient-specific and subtype-specific therapeutic hypotheses. Several large-scale studies, including those from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), aim to survey the landscape of genomic and molecular profiles of thousands of tumor samples in tens of different tumor types from generous patients. We analyze these informative genetic and molecular profiles to better understand the processes of oncogenesis, vulnerabilities to therapeutic interventions and tumor-subtype specific differences. Hypotheses can then be tested in focussed cell line and mouse model experiments and, if validated, advanced to clinical trials. To assist the general community of cancer biologists, we make available a generally useful feature map of essential information in the Cancer Genome Atlas via the information service cbioportal.org. Analysis and information services reported are based on the work of Niki Schultz, Giovanni Ciriello, Nils Weinhold, William Lee, Jian Jiong Gao, Rileen Sinha, Anders Jacobsen, Erik Larsson, Arman Aksoy, Gideon Dresdner, Benjamin Gross, several clinical research collaborators and the TCGA network.
Citation Format: Nikolaus Schultz, Chris Sander. Computational cancer genomics: Biological discovery and translation. [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 SY12-02. doi:10.1158/1538-7445.AM2013-SY12-02
Abstract SY16-01: Transcriptional regulation and epigenetics in zebrafish cancer.
Authors: Zon Leonard I. 
Published: August 2014

Abstract
Melanoma is a devastating disease for which few therapies lead to long term remission after metastasis has occurred. We have been using the zebrafish to model melanoma. A transgenic fish carrying human V600E BRAF mutation in combination with p53 mutation leads to a rapid melanoma model in the zebrafish. Using a transposon based approach, we have been able to overexpress particular potential oncogenes to look for acceleration of the melanoma. One such oncogene (SETDB1) is amplified in 30% of human melanomas and accelerates tumor rate in the zebrafish. Using a library of chromatin factors that are full length, we have been able to overexpress over 80 factors and found several new factors that activate and induce more melanoma. This approach has led to a fundamentally new insight into melanoma and epigenetic regulation. We also have found a chemical (leflunomide) that lowers nucleotide levels and induces a transcriptional pause of neural crest genes. Leflunomide and a BRAF inhibitor is now in clinical trial for patients with metastatic melanoma. To understand the mechanism of action, we have focused on PTEFb that is a kinase that regulates the elongation step in transcription. We found that the HEXIM complex is able to sequester PTEFb into an inactive state. HEXIM is a new tumor suppressor gene for melanoma. Our studies have led to a better understanding of transcription in melanoma and have developed a novel therapeutic that is being tested in the clinic.
Citation Format: Leonard I. Zon. Transcriptional regulation and epigenetics in zebrafish 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 SY16-01. doi:10.1158/1538-7445.AM2013-SY16-01