bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1800: Progesterone receptor attenuates STAT1-mediated interferon signaling in breast cancer
Authors: Goodman Merit , Trinca Gloria , Walter Katherine , Papachristou Evangelia , D'Santos Clive , Li Tianbao , Liu Qi , Lai Zhao , Chalise Prabhakar , Madan Rashna , Jin Victor , Carroll Jason , Hagan Christy 
Published: August 2018

Abstract
Why some tumors remain indolent and others progress to clinical relevance remains a major unanswered question in cancer biology. Interferon signaling in nascent tumors, mediated by STAT1, is a critical step through which the surveilling immune system can recognize and destroy developing tumors, thereby blocking their progression. We used an unbiased approach aimed at identifying nuclear protein interactions, called RIME, to identify novel progesterone receptor (PR) protein-protein interactions in T47D breast cancer cells. Using this technique, we identified a novel interaction between PR and STAT1. This interaction led to decreased interferon-induced STAT1 phosphorylation, a phenotype that was further potentiated in the presence of PR ligand. In human breast cancer samples, PR-positive tumors exhibited lower levels of phospho-STAT1 as compared to their PR-negative counterparts, indicating that this phenotype translates to human tumors. Breast cancer cells lacking PR expression exhibited higher levels of interferon-stimulated gene (ISG) RNA, the transcriptional endpoint of interferon activation, indicating that unliganded PR alone could decrease transcription of ISGs. Moreover, the absence of PR led to increased recruitment of STAT1, STAT2 and IRF9 (key transcription factors necessary for ISG transcription) to ISG promoters. These data indicate that PR, both in the presence and absence of ligand, attenuates interferon-induced STAT1 signaling, culminating in significantly abrogated activation of genes transcribed in response to interferons. PR-positive tumors may use downregulation of STAT1-mediated interferon signaling to escape immune surveillance, leading to the development of clinically relevant PR-positive tumors. Selective immune evasion of PR-positive tumors may be one explanation as to why over 70% of breast cancers are PR-positive at the time of diagnosis.
Citation Format: Merit Goodman, Gloria Trinca, Katherine Walter, Evangelia Papachristou, Clive D'Santos, Tianbao Li, Qi Liu, Zhao Lai, Prabhakar Chalise, Rashna Madan, Victor Jin, Jason Carroll, Christy Hagan. Progesterone receptor attenuates STAT1-mediated interferon signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1800.
Abstract 1811: O-GlcNAc-dependent regulation of progesterone receptor function in breast cancer
Authors: Trinca Gloria M. , Goodman Merit L. , Papachristou Evangelia K. , D'Santos Clive S. , Chalise Prabhakar , Madan Rashna , Slawson Chad , Hagan Christy R. 
Published: August 2018

Abstract
Emerging clinical trial data implicate progestins in the development of breast cancer. While the role for the progesterone receptor (PR) in this process remains controversial, it is clear that PR, a steroid-activated nuclear receptor, alters the transcriptional landscape of breast cancer. PR interacts with many different types of proteins, including transcriptional co-activators and co-repressors, transcription factors, nuclear receptors and proteins that post-translationally modify PR (i.e. kinases and phosphatases). Herein, we identify a novel interaction between PR and OGT, the enzyme that catalyzes the addition of a single N-acetylglucosamine sugar, referred to as O-GlcNAc, to acceptor serines and threonines in target proteins. This interaction between PR and OGT leads to the post-translational modification of PR by O-GlcNAc. Moreover, we show that O-GlcNAcylated PR is more transcriptionally active on PR-target genes, despite the observation that PR mRNA and protein levels are decreased when O-GlcNAc levels are high. O-GlcNAcylation in breast cancer is clinically relevant, as we show that O-GlcNAc levels are higher in breast cancer as compared to matched normal tissues, and PR-positive breast cancers have higher levels of OGT. These data predict that under conditions where O-GlcNAc levels are high (breast cancer), PR, through an interaction with the modifying enzyme OGT, will exhibit increased O-GlcNAcylation and potentiated transcriptional activity. Therapeutic strategies aimed at altering cellular O-GlcNAc levels may have profound effects on PR transcriptional activity in breast cancer.
Citation Format: Gloria M. Trinca, Merit L. Goodman, Evangelia K. Papachristou, Clive S. D'Santos, Prabhakar Chalise, Rashna Madan, Chad Slawson, Christy R. Hagan. O-GlcNAc-dependent regulation of progesterone receptor function in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1811.
Abstract 1824: Mechanisms of resistance to anti-EGFR/HER2 therapy in breast cancer
Authors: Borrero-García Luis Daniel , Vidal Brian , Dharmawardhane Suranganie 
Published: August 2018

Abstract
Therapy resistance to epidermal growth factor receptor family (EGFR and HER2) targeted therapies has been an obstacle for treatment success in breast cancer. Therefore, our goal is to investigate the mechanisms of resistance to these therapeutics and look for alternative ways to overcome such resistance. We previously created and characterized syngeneic gefitinib and lapatinib (EGFR and HER2 therapeutics) therapy resistant variants of the therapy sensitive SKBR3 human breast cancer cell line. We found that key mechanisms of resistance involved downregulation of miR-200a and upregulation of miR-221/222 families, which are known to regulate epithelial to mesenchymal transition (EMT). To validate the role of miR-221/222 in therapy resistance, western blots were performed for the miR-221/222 target Trichorhinophalangeal syndrome type I (TRPS1) protein. Downregulation of TRPS1 is known to promote EMT and metastasis. As expected, our results showed a downregulation of TRPS1 in the therapy resistant cells compare to the therapy sensitive cells. Since miR-200a was significantly downregulated in the therapy resistant cells, we ectopically expressed miR-200a in the EGFR therapy resistant SKBR3 cells using a lentiviral vector. MiR-200a expressing cells were selected by puromycin resistance. Preliminary data showed a decrease in the fold resistance of cells resistant to lapatinib transfected with lentiviral vector overexpressing miR-200a. These results suggest that overexpression of miR-200a in lapatinib resistant cells can be used to overcome therapy resistance in breast cancer.
Citation Format: Luis Daniel Borrero-García, Brian Vidal, Suranganie Dharmawardhane. Mechanisms of resistance to anti-EGFR/HER2 therapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1824.
Abstract 1834: Src inhibition overcomes neratinib resistance in HER2-positive breast cancer
Authors: Conlon Neil , Lowry Michelle , Breslin Susan , O'Driscoll Lorraine , Eustace Alexander J. , Crown John , O'Donovan Norma , Collins Denis M. 
Published: August 2018

Abstract
Introduction: Despite the recent successes of HER2-targeted therapies, drug resistance still represents a significant clinical problem. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been recently FDA approved for the extended adjuvant treatment of early-stage HER2-positive breast cancer and little is known of its mechanism of resistance in breast cancer. Using a neratinib-resistant cell line model of HER2-positive breast cancer, HCC1954-N, the aim of this study was to characterise cross-resistance to other HER-targeting tyrosine kinase inhibitors (TKIs) and investigate the role of Src in acquired neratinib resistance.
Methods: The effect of HER-family targeting TKIs neratinib, lapatinib, afatinib and, the Src inhibitor, dasatinib on proliferation of HCC1954-N and HCC1954-Par cells was assessed by acid phosphatase assays and three-dimensional Matrigel assays. Cell cycle progression was examined by flow cytometry using a propidium iodide assay. Caspase 3/7-Glo assay was used to assess apoptosis induction. To assess the prevention of the development of neratinib resistance, HCC1954 cells were treated twice weekly with neratinib, dasatinib, or the combination and stained with crystal violet when confluent.
Results: The HCC1954-N cell line was resistant to neratinib and to afatinib and lapatinib compared to parental HCC1954, but neratinib was still the most potent of the three anti-proliferative agents. The combination of neratinib and dasatinib was synergistic in the neratinib-resistant HCC1954-N cell line in both adherent (CI value = 0.1 ± 0.03) and three-dimensional (CI value = 0.36 ± 0.02) conditions. Neratinib plus dasatinib did not result in cell cycle arrest; however, the combination caused a significant increase in the sub-G1 cell cycle population (p value = 0.018), indicating induction of apoptosis. This was further validated by increased activation of caspase 3 and 7 (p value = 0.015) in HCC1954-N cells treated with neratinib plus dasatinib. The addition of dasatinib to neratinib treatment prevented the development of neratinib resistance in parental HCC1954 cells.
Conclusions: Further pre-clinical investigation of the combination of neratinib plus dasatinib is warranted as a potential therapeutic intervention for patients with neratinib-resistant HER2-positive breast cancer.
Citation Format: Neil Conlon, Michelle Lowry, Susan Breslin, Lorraine O'Driscoll, Alexander J. Eustace, John Crown, Norma O'Donovan, Denis M. Collins. Src inhibition overcomes neratinib resistance in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1834.
Abstract 1851: Combined inhibition of PARP and the unfolded protein response synergistically reduces viability in BRCA1-mutant breast cancer cells
Authors: Endress Jennifer E. , Harris Isaac S. , Stewart-Ornstein Jacob , Lahav Galit , Brugge Joan S. 
Published: August 2018

Abstract
As single agents, small molecule inhibitors of poly-ADP-ribose polymerase (PARP) have shown remarkable efficacy in BRCA1/2-mutant tumors due to their synthetic lethality in DNA damage response-deficient cells. While PARP inhibitors, such as olaparib, have gained FDA-approval for gynecological malignancies, recurrent disease remains a challenge. To identify drug combinations with the potential to improve the initial response to PARP inhibition, we carried out a high-throughput drug screen in which we examined the ability of olaparib to synergize with more than 500 small molecules in BRCA1-mutant breast cancer cells. The compounds investigated included not only conventional “anti-cancer” agents but also lesser-studied metabolic and stress-inducing drugs. All compounds were tested across 10-point dose curves using an image-based readout to avoid false positives/negatives associated with more traditional metabolic readouts of cell viability (i.e. Cell Titer Glo). This screening approach revealed that inhibition of the unfolded protein response (UPR) sensitizes breast cancer cells to PARP inhibition. We have further characterized interaction of one class of inhibitors that target IRE1 (inositol-requiring enzyme 1), which initiates adaptive responses to ER stress through unconventional mRNA splicing of the transcription factor X-box binding protein 1 (XBP1). Combining olaparib with an inhibitor of IRE1-mediated XBP1 splicing (STF-0831010) synergistically reduced cancer cell viability in BRCA1-mutant SUM149 breast cancer cells. This combination led to increased DNA damage, indicated by increased γ-H2AX staining. This study provides evidence that UPR inhibition sensitizes cells to PARP inhibition, suggesting a previously un-recognized connection between PARP inhibition and protein homeostasis. Furthermore, it identifies a potential new drug combination to increase the efficacy of PARP inhibitors in the clinic.
Citation Format: Jennifer E. Endress, Isaac S. Harris, Jacob Stewart-Ornstein, Galit Lahav, Joan S. Brugge. Combined inhibition of PARP and the unfolded protein response synergistically reduces viability in BRCA1-mutant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1851.
Abstract 1858: EDNRB isoform 3 confers temozolomide resistance in human melanoma cells by modulating membrane potential, reactive oxygen species and mitochondrial Ca2+
Authors: Cui Long , Liang Bo , Chen Xiaoting , Wang Chi Chiu 
Published: August 2018

Abstract
Background: The role of Endothelin receptor type B (EDNRB) isoform 3 involved in Temozolomide (TMZ) induced melanoma cell death has not yet been elucidated.
Methods: The subcellular localization of EDNRB isoform 3 was determined by confocal and immunoblotting assays. Silencing EDNRB isoform 3 was performed by CRISPR/Cas9. Apoptosis was assessed by Annexin V/PI staining and caspases 3/7/9 activity. Mitochondrial membrane potential, reactive oxygen species and mitochondrial Ca2+ were measured by flow cytometry. Apoptosis protein array was applied.
Results: Confocal and immunoblot analyses indicate mitochondrial localization of EDNRB isoform 3 and the first N-terminal (1-22) amino acids are sufficient for its mitochondrial targeting. EDNRB isoform 3 depleted A375 cells significantly inhibit apoptosis. EDNRB isoform 3 mediates chemoresistance appears to be acting via a mitochondrial apoptosis pathway as manifested by the prevention in mitochondrial depolarization, reduced reactive oxygen species, enhanced mitochondrial Ca2+ uptake and decreased caspase 9 activation. Additionally, apoptosis array shows that lack of EDNRB isoform 3 has relatively lower expression of phosphorylation of p53 at S392 and a slightly higher expression of Paraoxonase 2.
Conclusion: Our findings raise the possibility of targeting EDNRB isoform 3 as new therapeutic strategy in combination with TMZ for melanoma treatment.
Citation Format: Long Cui, Bo Liang, Xiaoting Chen, Chi Chiu Wang. EDNRB isoform 3 confers temozolomide resistance in human melanoma cells by modulating membrane potential, reactive oxygen species and mitochondrial Ca2+ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1858.
Abstract 1866: Small molecule NSC59984 is a radio-sensitizer dependent on ERK2 and DDR but independent of wild-type p53
Authors: Zhang Shengliang , Zhou Lanlan , Finnberg Niklas , El-Deiry Wafik 
Published: August 2018

Abstract
Radiotherapy is a common and effective therapeutic strategy applied to various types of tumors. Mutations that commonly occur in p53 as a tumor suppressor gene, are a hallmark of tumor, and confer cellular radio-resistance. Targeted therapy is considered as a promising approach to increase efficacy and specificity of radiotherapy. We explore utilization of a small molecule targeting mutant p53 to enhance efficacy of radiotherapy in colorectal cancer. Colorectal cancer cells carrying with mutant p53 were treated with NSC59984 followed by ionizing radiation treatment. Combined NSC59984 with radiation significantly reduced colony formation in mutant p53-expressing colorectal cancer cells in a dose-dependent manner, suggesting that NSC59984 enhances the efficacy of radiotherapy. NSC59984 induces mutant p53 degradation via the ERK2 pathway. We investigated the role of ERK2 in the efficacy of the combination of NSC59984 and radiation treatment. ERK2 blockade partially abrogated the effect of NSC59984 on the radio-sensitivity, and this correlated with the rescue of mutant p53. Our results suggest that NSC59984 increases the efficacy of radiotherapy via activation of ERK2 or ERK2-dependant mutant p53 degradation. Mutant p53 and ERK2 are important regulators involved in repair of DNA double-strand breaks. We examined the DNA damage response (DDR) system and found that reduced Rad51 protein in cells treated with NSC59984, and the Rad51 protein was increased by the blockade of the ERK2 pathway. On the basis of the above results, we conclude that small-molecule NSC59984 enhances cancer cell sensitivity to radiotherapy via the ERK2 pathway and effects on DDR.
Citation Format: Shengliang Zhang, Lanlan Zhou, Niklas Finnberg, Wafik El-Deiry. Small molecule NSC59984 is a radio-sensitizer dependent on ERK2 and DDR but independent of wild-type p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1866.
Abstract 1894: Identification of novel OTX015-containing combinations for lymphoma treatment
Authors: Gaudio Eugenio , Tarantelli Chiara , Spriano Filippo , Arribas Alberto J. , Cascione Luciano , Zucca Emanuele , Stathis Anastasios , Bertoni Francesco 
Published: August 2018

Abstract
Introduction. Epigenetics represents and intriguing target of therapy for lymphomas. The epigenetic mechanisms are regulated by several players (e.g. HDAC, HAT, BET) and among them the BET proteins became of interest a few years ago with demonstrated preclinical anti-cancer activity with the first compounds and early clinical responses first in class clinical-grade BET inhibitor OTX015 (MK-8628/birabresib). Despite a widespread anti-proliferative activity, the cytotoxicity effect of BET inhibitors is limited, and, here, we aimed to identify drugs that improve OTX015 activity performing a screening with the BET inhibitor with a library 348 compounds in two lymphoma cell lines.
Methods. Two cell lines derived from germinal center B cell (GCB) diffuse large B cell lymphoma (DLBCL) (OCI-LY-19 and WSU-DLCL2) were exposed to OTX015 (single dose, 100 nM) in combination with two different doses (20 and 1,000 nM) of 348 compounds. Compounds giving a 1.5-fold decreased proliferation with the combination than with the individual compounds were further evaluated in two additional lymphoma cell lines, exposed (72h) to increasing doses of OTX015 alone and in combination with increasing doses of other selected compounds. Synergy was assessed with Chou-Talalay combination index (CI): synergism (&lt;0.9), additive (0.9-1.1), antagonism/no benefit (&gt; 1.1).
Results. OCI-LY-19 and WSU-DLCL2 were treated with OTX015 (100 nM) and 348 compounds as single agents and in combination. The combinations of OTX015 with a series of compounds achieved improved anti-tumor activity than single agents. Besides HDAC and mTOR inhibitors, in accordance with what previously reported (Boi, Gaudio, Bonetti et al, Clinical Cancer Res 2015), the ABL/SRC inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209 and the LRRK2 inhibitor LRRK2-IN appeared interesting combination partners. These screening results were validated in the DLBCL cell lines with targeted experiments, as well as in chronic lymphocytic leukemia (CLL) (OTX015 plus MK-2206) and mantle cell lymphoma (MCL) (REC1) (Dasatinib, LRRK2-IN). Experiments in additional cell lines and assessing the effects on the apoptosis are on-going and will be presented.
Conclusion. A chemical screening has identified novel OTX015-containing combinations active in lymphoma cell lines that are worth of further investigations.
Work supported by a San Salvatore Foundation grant.
Citation Format: Eugenio Gaudio, Chiara Tarantelli, Filippo Spriano, Alberto J. Arribas, Luciano Cascione, Emanuele Zucca, Anastasios Stathis, Francesco Bertoni. Identification of novel OTX015-containing combinations for lymphoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1894.
Abstract 1902: Potential role of DYRK family kinases in harmine-induced apoptosis in neuroblastoma
Authors: Uhl Katie L. , Schultz Chad R. , Geerts Dirk , Bachmann Andre S. 
Published: August 2018

Abstract
The purpose of this study was to determine the effect of the natural product Harmine in human neuroblastoma (NB). NB is an early childhood malignancy arising from the developing peripheral nervous system. In up to 25% of cases MYCN gene amplification is correlated to high tumor stage and poor patient prognosis. High stage NB relapses frequently in spite of multimodal therapy and is then virtually untreatable. There is a clear need for specific, novel therapeutics. Harmine is a tricyclic β-carboline alkaloid from the harmal plant with cytostatic and cytotoxic effects on tumor cells. It is capable of blocking the activity of mitogen activate protein kinase (MAPK) and the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK) family proteins. These kinases inhibit apoptosis and encourage proliferation. Four human NB cell lines were used to study the effects of Harmine treatment: SK-N-BE(2)-C and KELLY (MYCN amplified) as well as SK-N-AS and SK-N-FI (MYCN single copy). Molecular interaction models of Harmine bound to DYRK family kinases were generated by computational docking using x-ray structures. The anti-cancer properties of Harmine were analyzed by real-time cell viability assays, in a dose-dependent manner, over a 72 hour period. The IC50 values were 169.9, 170.8, and 791.7 μM for SK-N-BE(2)-C, KELLY, and SK-N-FI, respectively, after 72 hours. Apoptosis assays for caspase activation, PARP cleavage, and annexin V induction, were performed using Western blot and flow cytometry. NB cell line exposure to 100 μM Harmine resulted in caspase-3/7 and caspase 9 activation, PARP cleavage, and annexin V-positive stained cells as early as 24 hours after treatment, indicating apoptosis induction. These results led us to investigate the clinical correlations of DYRK family gene expression in NB tumors. The patient results support our hypothesis that Harmine induces NB cell death through a cellular mechanism that involves DYRK family kinases and triggers caspase-mediated apoptosis.
Citation Format: Katie L. Uhl, Chad R. Schultz, Dirk Geerts, Andre S. Bachmann. Potential role of DYRK family kinases in harmine-induced apoptosis in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1902.