bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4757: A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer
Authors: Joseph James D. , Darimont Beatrice , Govek Steven , Brigham Dan , Qian Jing , Sensintaffar John , Shao Gang , Aparicio Anna , Kahraman Mehmet , Lai Andiliy , Lee Kyoung-Jin , Lu Nhin , Nagasawa Johnny , Moon Michael , Rix Peter , Smith Nick , Hager Jeff 
Published: May 2015

Abstract
80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can be activated in the absence of estrogens via point mutations in ERα or cellular signaling pathways supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling.
We have identified two novel series of non-steroidal ERα antagonists, series I exemplified by ARN-810, now in clinical trials for treatment of endocrine resistant breast cancer, and series II, both of which induce degradation of ERα at picomolar concentrations resulting in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show that both series induce ERα conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. In vitro, both ligand series are active on wild-type and the constitutively active ERα mutants found in endocrine resistant breast cancer patients. Importantly, these compounds yield tumor regression in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Based on their unique in vitro profile, and good pharmacokinetics following oral dosing, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance.
Citation Format: James D. Joseph, Beatrice Darimont, Steven Govek, Dan Brigham, Jing Qian, John Sensintaffar, Gang Shao, Anna Aparicio, Mehmet Kahraman, Andiliy Lai, Kyoung-Jin Lee, Nhin Lu, Johnny Nagasawa, Michael Moon, Peter Rix, Nick Smith, Jeff Hager. A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant 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 4757. doi:10.1158/1538-7445.AM2014-4757
Abstract 477: The dynamic changes of KLF4 in the oral squamous cell carcinogenesis
Authors: Liu Man , Su Ying , Zhang Xinyan 
Published: May 2015

Abstract
KLF4 (formerly GKLF) is a zinc-finger transcription factor expressed in the epithelia of the skin, lungs, gastrointestinal tract and several other organs. In vitro studies have suggested that KLF4 plays an important role in cell proliferation and/or differentiation. Several studies implied that KLF4 is associated with both tumour suppression and oncogenesis, but the function of KLF4 in the oral carcinogenesis has not been investigated. To address this issue we have generated an animal model of experimental tongue cancerous lesions in C57BL/6J mouse by using carcinogen 4-nitroquinoline-1-oxide (4NQO) in drinking water .And we detected the KLF4 expression in mouse tongue precancerous and cancer lesions by immunohistochemistry. Normally KLF4 was strongly expressed in the nuclei of mice tongue epithelial cells. The staining of KLF4 was gradually decreased from normal epithelial to hyperplasia to dysplasia, and markedly decreased in the squamous cell carcinomas. The results indicated that KLF4 could served as a tumour-suppressor functions in the oral carcinogenesis.
Citation Format: Man Liu, Ying Su, Xinyan Zhang. The dynamic changes of KLF4 in the oral squamous cell carcinogenesis. [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 477. doi:10.1158/1538-7445.AM2014-477
Abstract 4772: Novel transforming ErbB2 mutations in leukemia
Authors: Keck Jamie , Druker Brian 
Published: May 2015

Abstract
The ErbB2/Her2 type 1 transmembrane receptor tyrosine kinase heterodimerizes with ligand-bound EGFR, ErbB3, or ErbB4 to activate multiple signaling pathways. ErbB2 is commonly amplified in breast, stomach, cervical, and bladder tumors and point mutations are found in many cancers. However, little is known about aberrant ErbB2 in hematologic malignancies. Deep sequencing was performed on primary leukemia patient samples and point mutations were identified within the extracellular receptor binding domains and the intracellular C-terminal region of ErbB2. Expression of these mutations in NIH 3T3 fibroblasts exhibited a transformed morphological phenotype and in Ba/F3 pro-B cells led to IL-3-independent growth and differential signaling within the MAPK and PI3K pathways. Further characterization of the mutations will assess migration properties, differential sensitivity to ErbB-family drug inhibitors, and heterodimer formation using bimolecular fluorescence complementation microscopy. Overall, this work identifies novel transforming ErbB2 mutations and may provide insight into effective therapy for leukemia patients harboring ErbB2 mutations.
Citation Format: Jamie Keck, Brian Druker. Novel transforming ErbB2 mutations in leukemia. [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 4772. doi:10.1158/1538-7445.AM2014-4772
Abstract 4773: Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways
Authors: Rothenberg Stephen Michael , Concannon Kyle , Cullen Sarah , Turke Alexa B. , Faber Anthony C. , Engelman Jeffrey A. , Maheswaran Shyamala , Haber Daniel A. 
Published: May 2015

Abstract
Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to SOX2 induction and repression of the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death and may contribute to the acquisition of drug resistance.
Citation Format: Stephen Michael Rothenberg, Kyle Concannon, Sarah Cullen, Alexa B. Turke, Anthony C. Faber, Jeffrey A. Engelman, Shyamala Maheswaran, Daniel A. Haber. Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways. [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 4773. doi:10.1158/1538-7445.AM2014-4773
Abstract 4774: The antitumor effects of PI3K beta inhibitors in PTEN negative prostate cancer are enhanced by inhibition of reactivated PI3K alpha signaling
Authors: Schwartz Sarit , Carver Brett S. , Wongvipat John , Rodrik-Outmezguine Vanessa , Stanchina Elisa D. , Trigwell Cath , Barry Simon , Baselga Jose , Chandarlapaty Sarat , Scher Howard I. , Sawyers Charles L. , Rosen Neal 
Published: May 2015

Abstract
The PI3K pathway is dysregulated in many cancers via selective activation of class 1 isoforms. In tumors with deficient PTEN function, signaling is driven by PI3K beta. We show here that a selective inhibitor of PI3K beta inhibits the AKT/mTOR pathway in tumors with defective PTEN function, but is ineffective in those where the pathway is driven by receptor tyrosine kinases. However, inhibition of PI3K signaling by PI3K beta inhibitors is limited by relief of AKT/mTOR dependent feedback and reactivation of IGF1R and other receptors. This results in activation of PI3K alpha and a rebound of PI3K-AKT signaling. This rebound is suppressed and tumor cell inhibition is enhanced with combined inhibition of PI3K alpha and beta. Combined administration of isoform selective PI3K inhibitors may more effectively inhibit the pathway than pan-PI3K inhibitors because of the greater selectivity and decreased off-target toxicity of the former.
In PTEN deficient models of prostate cancer, triple therapy with PI3K alpha and beta selective inhibitors combined with a potent androgen receptor inhibitor suppresses the reciprocal feedback activation of both pathways and results in marked (complete) eradication of tumors in vivo.
Citation Format: Sarit Schwartz, Brett S. Carver, John Wongvipat, Vanessa Rodrik-Outmezguine, Elisa De Stanchina, Cath Trigwell, Simon Barry, Jose Baselga, Sarat Chandarlapaty, Howard I. Scher, Charles L. Sawyers, Neal Rosen. The antitumor effects of PI3K beta inhibitors in PTEN negative prostate cancer are enhanced by inhibition of reactivated PI3K alpha signaling. [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 4774. doi:10.1158/1538-7445.AM2014-4774
Abstract 478: Predicting interactome networks perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia
Authors: Hajingabo Leon , Daakour Sarah , Martin Maud , Grausenburger Reinhard , Panzer-Grümayer Renate , Dequiedt Franck , Helden Jacques Van , Twizere Jean-Claude , Simonis Nicolas 
Published: May 2015

Abstract
Genomic variations such point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and as therapeutic targets. However, predicting the functional impact of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes likely result in complex molecular interaction networks. Using as models three different chromosomal translocations ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and E2A-PBX1 (TCF3-PBX1) frequently found in B-cell acute lymphoblastic leukemia (B-ALL), we develop an approach to extract from gene expression changes, perturbed molecular interactions. We show that the Myc and JunD transcriptional circuits are specifically deregulated following TEL-AML1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and TEL-AML1 acute lymphoblastic leukemia.
Note: This abstract was not presented at the meeting.
Citation Format: Leon Hajingabo, Sarah Daakour, Maud Martin, Reinhard Grausenburger, Renate Panzer-Grümayer, Franck Dequiedt, Jacques Van Helden, Jean-Claude Twizere, Nicolas Simonis. Predicting interactome networks perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia. [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 478. doi:10.1158/1538-7445.AM2014-478
Abstract 4784: Selective bioluminogenic HDAC activity assays for profiling HDAC inhibitors
Authors: Kupcho Kevin R. , Evans Nathan J. , Niles Andrew L. , Kirkland Thomas A. , Lazar Dan F. 
Published: May 2015

Abstract
Histone deacetylases (HDACs) play critical roles in the regulation of gene transcription and cell signaling events by deacetylating histones and other important non-histone substrates. Aberrant increases in HDAC enzyme activities are therefore implicated in a number of human infirmities, including cancers, metabolic disease and neurodegeneration. Fortunately, HDAC enzymes represent attractive pharmacological targets because they are readily tractable with small molecule inhibitors. In fact, several HDAC inhibitors (HDACi) have recently proceeded through (or are near) the FDA approval process for the treatment of hematologic malignancies. However, the promise of clinical HDACi therapy has been hampered by significant dose-limiting toxicities. These off-target effects have led to a renewed focus on basic HDAC biology and the development of isoenzyme-specific HDAC inhibitors which could avoid off-target effects. To help facilitate the discovery of compounds with better defined selectivity profiles, we have developed lysine deacetylase assays that selectively measure specific isoenzyme activities in cells, extracts, or purified recombinant preparations. These assays are based on substrates that are selective due to a combination of extended peptide sequence and novel chemical modifications. Deacetylase activity is measured by delivering a single, pro-luminogenic, homogeneous assay reagent to assay wells, resulting in luminescence proportional to HDAC activity. In addition to being isoenzyme selective, these novel substrates are cell permeable allowing for lytic and non-lytic cell-based HDAC assays. Lastly, these assays are also fully compatible with fluorescent viability and/or cytotoxicity assays. This provides additional flexibility for multiplexed formats which examine not only selective HDAC inhibition, but the functional consequences they exert on cell health.
Citation Format: Kevin R. Kupcho, Nathan J. Evans, Andrew L. Niles, Thomas A. Kirkland, Dan F. Lazar. Selective bioluminogenic HDAC activity assays for profiling HDAC inhibitors. [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 4784. doi:10.1158/1538-7445.AM2014-4784
Abstract 4785: miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression
Authors: Ferracin Manuela , Bassi Cristian , Pedriali Massimo , Pagotto Sara , D'Abundo Lucilla , Zagatti Barbara , Volpato Stefano , Querzoli Patrizia , Negrini Massimo 
Published: May 2015

Abstract
Background: The microRNA 125b is a double-faced gene expression regulator described both as a tumor suppressor gene (in solid tumors) and an oncogene (in hematologic malignancies). In human breast cancer, it is one of the most down-regulated miRNAs and is able to modulate ERBB2/3 expression. Here, we investigated its targets in breast cancer cell lines after miRNA-mimic transfection. We examined the interactions of the validated targets with ERBB2 oncogene and the correlation of miR-125b expression with clinical variables.
Methods: MiR-125b possible targets were identified after transfecting a miRNA-mimic in MCF7 cell line and analyzing gene expression modifications with Agilent microarrays and Sylamer bioinformatic tool. Erythropoietin (EPO) and its receptor (EPOR) were validated as targets of miR-125b by luciferase assay and their expression was assessed by RT-qPCR in 42 breast cancers and 13 normal samples. The molecular talk between EPOR and ERBB2 transcripts, through miR-125b, was explored transfecting MDA-MD-453 and MDA-MB-157 with ERBB2 RNA and using RT-qPCR.
Results: We identified a panel of genes down-regulated after miR-125b transfection and putative targets of miR-125b. Among them, we validated erythropoietin (EPO) and its receptor (EPOR) - frequently overexpressed in breast cancer - as true targets of miR-125b. Moreover, we explored possible correlations with clinical variables and we found a down-regulation of miR-125b in metastatic breast cancers and a significant positive correlation between EPOR and ERBB2/HER2 levels, that are both targets of miR-125b and function as competing endogenous RNAs (ceRNAs).
Conclusions: Taken together our results show a mechanism for EPO/EPOR and ERBB2 co-regulation in breast cancer and confirm the importance of miR-125b in controlling clinically-relevant cancer features.
Citation Format: Manuela Ferracin, Cristian Bassi, Massimo Pedriali, Sara Pagotto, Lucilla D'Abundo, Barbara Zagatti, Stefano Volpato, Patrizia Querzoli, Massimo Negrini. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. [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 4785. doi:10.1158/1538-7445.AM2014-4785
Abstract 4786: Circulating miR-21, miR-146a and miR-210 levels in plasma are associated with clinical outcome in breast cancer
Authors: Sourvinou Ioanna S. , Markou Athina , Malamos Nikolaos , Georgoulias Vasilis , Lianidou Εvi S. 
Published: May 2015

Abstract
Introduction: The discovery of novel non-invasive tumor biomarkers for early diagnosis, prognosis and therapy monitoring remains an undeniable imperative necessity. Circulating miRNAs have recently attracted a lot of interest as novel promising tumor biomarkers. In the present study, we investigated the expression levels of three cancer-associated miRNAs in plasma and evaluated their prognostic significance in breast cancer.
Materials and Methods: We examined the expression levels of miR-21, miR-146a and miR-210 in plasma samples of 134 breast cancer patients (57 patients with verified metastasis and 77 patients with operable breast cancer) and 20 healthy individuals. Circulating miRNAs were isolated from 200μL of plasma using mirVana PARIS kit and in each sample 25fmol of the synthetic cel-miR-39 were spiked as exogenous control. For the quantification of plasma miRNAs, a stem-loop cDNA approach and TaqMan real time PCR (LightCycler 2, Roche Applied Science) were used. The normalization procedure was based on a combination of cel-miR-39 as exogenous control and hsa-miR-191 as endogenous control. Relative expression of circulating miRNAs in plasma was evaluated as previously described (Sourvinou et al., J. of Mol. Diagn, 2013).
Results: Our results indicate that the expression levels of all three circulating miRNAs are significantly increased in plasma both in operable and metastasis verified breast cancer patients in comparison to those of healthy individuals (p&lt;0.001). The expression levels of plasma miR-210 are slightly increased in patients with operable breast cancer in respect to patients with verified metastasis (p=0.034). In patients with verified metastasis, Kaplan-Meier survival analysis demonstrated an association between elevated levels of plasma miR-21 and overall survival (OS) (p= 0.001) and there was a trend with disease-free interval (DFI) (p=0.053). Concerning miR-146a, increased plasma expression levels were correlated with short OS (p=0.029), but there was no correlation with DFI (p=0.914). Finally, respecting miR-210, Kaplan-Meier survival analysis did not show any association with OS or DFI of these patients.
Conclusions: Our results indicate that quantification of circulating miR-21 and miR-146a in plasma are promising prognostic biomarkers in breast cancer and should be further evaluated in a large number of patients.
Citation Format: Ioanna S. Sourvinou, Athina Markou, Nikolaos Malamos, Vasilis Georgoulias, Εvi S. Lianidou. Circulating miR-21, miR-146a and miR-210 levels in plasma are associated with clinical outcome 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 4786. doi:10.1158/1538-7445.AM2014-4786
Abstract 4791: The role of microRNA-15a/16 in early B1 cell development in a mouse model of chronic lymphocytic leukemia
Authors: Underbayev Chingiz , Kasar Siddha , Degheidy Heba , Marti Gerald , Lightfoote Marilyn , Raveche Elizabeth 
Published: May 2015

Abstract
New Zealand Black (NZB) mouse is a de-novo model of chronic lymphocytic leukemia (CLL) that has been studied as a model of B-cell lymphoproliferative disorder. In most human CLL and NZB there is decreased expression of the microRNA miR15a/16. In NZB (and some CLL patients) this is due a point mutation six bases downstream from pre-miR-16 region. In both NZB mouse model and human CLL, the disease is characterized by the presence of a malignant clone of B-1 cells expressing dull levels of CD5 (T cell marker), CD11b (myeloid marker) and B220 (B cell marker). In this report we investigated the molecular pathways that result in increased B-1 lineage development in the mouse model of CLL. Initially we observed that in NZB, the B-1 lineage cells had reduced expression of Pu.1 when compared to NZB B-2 cells. PU.1 is a transcription factor required for B lineage differentiation and PU.1 knockout mice were previously found by others to have only B-1 lineage cell differentiation. To study early B1/B2 divergent cell development pathways in the context of CLL and shed light on the potential malignant cell origin of this disease, we generated induced pluripotent stem cells (iPS) from NZB spleen stromal fibroblasts. Our in vivo and in vitro studies on NZB iPS and hematopoietic progenitors (LSK) differentiation towards B-cell lineage cells followed by multicolor flow based cell sorting revealed a substantial block in the maturation of NZB iPS cells compared to wild type counterparts. Preliminary data using congenic NZB mice with corrected mir-15a/16-1 locus demonstrated that normal levels of miR-15a/16 regulate B-cell differentiation towards a higher expression of PU.1 and B220 (CD45R) and lower levels of CD11b suggestive of an enhanced B2 cell maturation pathway. Our results support the hypothesis that decreased miR-15a plays a role in B1 lymphocyte development bias in the course of B cell maturation by regulating the expression of a number of genes such as B220, PU.1 and CD11b. This work will help further uncover early molecular events which determine the increased B1 versus B2 lineage commitment associated with low levels of miR-15a/16 as an initial lesion in the development of CLL.
Citation Format: Chingiz Underbayev, Siddha Kasar, Heba Degheidy, Gerald Marti, Marilyn Lightfoote, Elizabeth Raveche. The role of microRNA-15a/16 in early B1 cell development in a mouse model of chronic lymphocytic leukemia. [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 4791. doi:10.1158/1538-7445.AM2014-4791