bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 82: CYP3A4 promotes mammary carcinoma angiogenesis in a cell iIntrinsic fashion.
Authors: Guo Zhijun , Norris Beverly , Henriksen Jonathan , Morgan Monique , Maher Michael , Schumacher Robert , Bliss Robin , Chu Haitao , Gupta Kalpna , Schmechel Stephen , Potter David 
Published: August 2014

Abstract
Cytochrome P450 3A4 (CYP3A4) has been recently been implicated in breast cancer cell growth and survival, but the role of cell intrinsic CYP3A4 in breast cancer cell engraftment and angiogenesis is unknown. Previously, we have characterized CYP3A4 knock down lines in which CYP3A4 is stably suppressed [J Biol Chem. 2011 May 20;286(20):17543-59]. The CYP3A4 knock down lines exhibit reduced proliferation and clonogenicity in vitro. We therefore tested in an estradiol dependent nude mouse mammary fat pad xenograft model whether the MCF-7 3-18 line (CYP3A4 shRNA), in which CYP3A4 protein levels are suppressed by 60%, exhibits reduced growth compared to a non-target line MCF-7 NT2. Before implantation, the suppression of CYP3A4 mRNA in the shRNA compared to NT2 cells was confirmed by qPCR. After 46 days of monitored tumor growth, the MCF-7 NT2 tumors exhibited a median size of 27±3 mm3 (median±SEM) compared to 2±0.6 mm3 for the MCF-7 CYP3A4 shRNA tumors. Tumor growth was modeled by a Gompertzian method and the difference was statistically significant (P=0.0018). The mammary fat pads were removed after sacrifice at the end of the experiment, inked, oriented and subjected to z-sectioning. All mice exhibited tumors. The CYP3A4 shRNA tumors exhibited necrosis (5 of 6 evaluable mice) whereas the NT2 control tumors did not (0 of 6 evaluable mice) (P=0.0152; two tailed Fisher's exact test). Angiogenesis was measured by CD31 immunohistochemical staining using an automated microvessel image analysis algorithm (Image Analysis Toolbox, Aperio Technologies) allowing measurement of percentage of area occupied by CD31 staining cells at the cortex of tumor nodules. Percent area occupied by CD31 positive cells was 2.69±0.46 vs. 0.67±0.64 (mean±SEM) (P=0.033). Together, these results suggest that cell intrinsic CYP3A4 is important for mammary carcinoma growth and angiogenesis in a xenograft model.
Citation Format: Zhijun Guo, Beverly Norris, Jonathan Henriksen, Monique Morgan, Michael Maher, Robert Schumacher, Robin Bliss, Haitao Chu, Kalpna Gupta, Stephen Schmechel, David Potter. CYP3A4 promotes mammary carcinoma angiogenesis in a cell iIntrinsic fashion. [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 82. doi:10.1158/1538-7445.AM2013-82
Abstract 822: The molecular diversity of Luminal A breast cancer.
Authors: Giovanni Ciriello , Perou Charles M. , Sander Chris , Schultz Nikolaus 
Published: August 2014

Abstract
Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from nearly 1000 Luminal A tumors from multiple studies, we identified at least four major subtypes defined by distinct copy-number and mutation profiles. Here we show an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling. These genomic alterations lead to a worse clinical prognosis. Copy number heterogeneity comes in tandem with distinct mutation spectra. We find a prevalence of PIK3CA, GATA3, and AKT1 mutations in the subtypes characterized by relatively diploid genomes subtypes.
Moreover, we highlight a strong association between MAP3K1 mutations and gains and losses of chromosomes 8 and 16. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations are prevalent in Luminal A tumors and may predict response to endocrine therapy. Our work shows how comprehensive genomic characterization of tumor subtypes is fundamental to inform clinical trials and to move towards personalized therapies.
Figure 1: Luminal A subtypes as determined by copy-number clustering.
Citation Format: Ciriello Giovanni, Charles M. Perou, Chris Sander, Nikolaus Schultz. The molecular diversity of Luminal A breast 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 822. doi:10.1158/1538-7445.AM2013-822
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 837: Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells.
Authors: Tchoghandjian Aurelie , Jennewein Claudia , Eckhardt Ines , Rajalingam Krishna , Fulda Simone 
Published: August 2014

Abstract
Since inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the Smac mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical NF-κB signaling and a TNFα/TNFR1 autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth in vivo underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cIAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-κB DNA binding and enhanced NF-κB transcriptional activity. EMSA supershift shows that the NF-κB DNA binding subunits consist of p50, p52 and RelB further confirming activation of the non-canonical NF-κB pathway. BV6-stimulated NF-κB activation leads to elevated mRNA levels of TNFα and additional NF-κB target genes involved in migration (i.e. IL-8, MCP-1, CXCR4) and invasion (i.e. MMP9). Importantly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-κB signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-κB target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNFα autocrine/paracrine loop by the TNFα-blocking antibody Enbrel or by knockdown of TNFR1 abrogates the BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-κB signaling, our findings have
Citation Format: Aurelie Tchoghandjian, Claudia Jennewein, Ines Eckhardt, Krishna Rajalingam, Simone Fulda. Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells. [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 837. doi:10.1158/1538-7445.AM2013-837
Abstract 846: ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells .
Authors: Chetram Mahandranauth A. , Jones Kia J. , Coke Christopher , Don-Salu-Hewage Ayesha , Bethea Danaya A. , Hinton Cimona V. 
Published: August 2014

Abstract
Reactive oxygen species (ROS) play a central role in oxidative stress, which leads to the onset of diseases, such as cancer. Furthermore, ROS contributes to the delicate balance between tumor cell survival and death. However, the mechanisms by which tumor cells decide to elicit survival or death signals during oxidative stress are not completely understood. We have previously reported that ROS enhanced tumorigenic functions in prostate cancer cells, such as cell migration and invasion, which depended on CXCR4 and AKT signaling. Here, we report a novel mechanism by which ROS facilitated cell death through activation of AKT. We initially observed that ROS increased expression of phosphorylated AKT (p-AKT) in 22Rv1 human prostate cancer cells. The tumor suppressor PTEN, a negative regulator of AKT signaling, was rendered catalytically inactive through oxidation by ROS, although the expression levels remained consistent. Despite these events, cells still underwent apoptosis. Further investigation into apoptosis revealed that expression of the tumor suppressor pVHL increased, with concomitant decreased expression of HIF1α. Further investigation into pVHL during apoptosis revealed that the tumor suppressor becomes phosphorylated at S111 prior to activity; S111 is within a target motif (RXXS) forphosphorylation by AKT kinase. We then determined that pVHL and p-AKT associated in vitro via co-immunoprecipitation assay. Moreover, knockdown of pVHL by siRNA rescued HIF1α protein expression and rescued cells from apoptosis, which was determined by Annexin-V and cleaved-PARP. Collectively, our study suggests that in the context of oxidative stress, activatedAKT facilitated apoptosis by inducing pVHL function. Moreover, our studies suggest a novel paradigm for AKT-that it may participate in tumor suppressor rather than oncogenesis.
Citation Format: Mahandranauth A. Chetram, Kia J. Jones, Christopher Coke, Ayesha Don-Salu-Hewage, Danaya A. Bethea, Cimona V. Hinton. ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells . [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 846. doi:10.1158/1538-7445.AM2013-846
Abstract 851: 14-3-3z-mediated suppression of tumor cell death.
Authors: Weerasekara Vajira K. , Mortenson Jeffrey B. , Andersen Joshua L. 
Published: August 2014

Abstract
For many cancer patients, cytotoxic chemotherapy is the primary treatment option. While the goal of these treatments is to induce tumor cell apoptosis, treatments too often fail as tumor cells possess the dynamic ability to subvert cell death and become chemoresistant. We are interested in determining the mechanisms by which tumors develop chemoresistance, with the goal of identifying potential therapeutic targets/pathways to increase the efficacy of chemotherapy. One context in which tumor cells are though to gain.14-3-3ζ is a small acidic protein that binds to phospho-serine proteins. 14-3-3ζ binding can have wide ranging effects, from the activation of enzyme function, to the orchestration of protein-protein interactions. 14-3-3ζ is highly expressed in many cancer types, and high levels of expression have been shown to correlate with the aggressiveness of tumors and lower rates of patient survival (1). However, the mechanisms by which 14-3-3ζ may promote tumor growth/tumor cell survival have yet to be determined. In this study we show that siRNA-mediated depletion of 14-3-3ζ potently sensitizes breast tumor cells to apoptosis induced by metabolic stress (e.g., hypoxia and glucose withdrawal_stresses commonly found within solid tumors) and chemotherapy. Moreover, gel filtration data suggest that metabolic cell stress induces a shift in 14-3-3ζ from high to lower molecular weight protein complexes. Drawing from these data, we performed a proteomics experiment to characterize 14-3-3ζ interactors under these conditions. We found that 14-3-3ζ associates with numerous pro-glycolysis- and cell growth-regulating enzymes (several of which are novel 14-3-3ζ interactors), and under conditions of metabolic stress, many of these interactions are diminished or lost. We are currently examining the functional consequences of these dynamic 14-3-3z interactions with respect to tumor cell survival. Together, our data suggest that 14-3-3ζ may play an apical role in regulating the metabolic response to stress, and provide insight into the mechanism by which 14-3-3ζ promotes tumor growth and survival.
Citation Format: Vajira K. Weerasekara, Jeffrey B. Mortenson, Joshua L. Andersen. 14-3-3z-mediated suppression of tumor cell death. [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 851. doi:10.1158/1538-7445.AM2013-851
Abstract 853: Inhibition of the nuclear transport protein CRM1 induces human breast cancer cell death by regulating survivin degradation.
Authors: Cheng Yan , Holloway Michael , Nguyen Kevin , Kauffman Michael , Shacham Sharon , Altura Rachel A. 
Published: August 2014

Abstract
Survivin is a member of the inhibitor of apoptosis protein (IAP) family based on its N-terminal baculovirus IAP repeat (BIR) domain. The protein is largely undetectable in differentiated tissues, but is highly expressed in most human tumors. Its cytoplasmic expression in these tumors correlates with reduced tumor cell death, increased resistance to cancer therapy, and decreased patient survival. Survivin is actively exported into the cytoplasm exclusively by the chromosomal region maintenance 1 (CRM1/Exportin1) protein, one of seven known nuclear export proteins. CRM1 binds to the canonical nuclear export signal (NES) domain within the survivin protein. Inhibition of CRM1-mediated nuclear export has been suggested as a novel cancer therapeutic strategy that restores the tumor suppressor function of multiple nuclear proteins. Here, we investigated the anti-tumor mechanisms of two novel, drug-like CRM1 inhibitors, KPT-185 and KPT-276, in estrogen-receptor positive and triple negative breast cancer cell lines. Tumor and control cells were treated with varying doses of the KPT compounds over time. Cell proliferation and apoptosis were measured using standard assays. Survivin localization and expression in the presence and absence of the KPT drugs was assessed by immunofluorescence microscopy and cell fractionation. Breast cancer cell lines were engineered to express higher or lower levels of Survivin to determine the contribution of Survivin inhibition to the anti-tumor effects of the CRM1 inhibitors. Results showed that the KPT compounds have potent anti-proliferative properties and that they induce time- and dose-dependent apoptosis. KPT-185 and KPT-276 initially enhanced nuclear Survivin expression but produced a decrease in total cellular Survivin levels at later time points. Survivin protein degraded at a faster rate following KPT treatment, which was blocked by treatment with proteasome inhibitors. Knockdown of Survivin increased KPT-mediated cell apoptosis while exogenous expression of Survivin rescued cells from KPT-mediated apoptosis. In summary, our data demonstrate that inhibition of nuclear export by CRM1 inhibition suppresses breast tumor cell growth and enhances tumor cell death, in part through specific targeting of the Survivin-CRM1 complex.
Citation Format: Yan Cheng, Michael Holloway, Kevin Nguyen, Michael Kauffman, Sharon Shacham, Rachel A. Altura. Inhibition of the nuclear transport protein CRM1 induces human breast cancer cell death by regulating survivin degradation. [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 853. doi:10.1158/1538-7445.AM2013-853
Abstract 889: Growth differentiation factor 15 causes increased invasiveness and EMT in HER2-overexpressing breast cancer via activation of p38 MAPK.
Authors: Joshi Jayashree P. , Chen Zhengjia , Nahta Rita 
Published: August 2014

Abstract
HER2 overexpression in breast cancer is frequently associated with aggressive and metastatic disease. De novo and acquired resistance to the first line therapy trastuzumab are major clinical issues that need to be addressed. We recently reported that the cytokine growth differentiation factor 15 (GDF15) is overexpressed in HER2-overexpressing breast cancer cell lines that have acquired or primary resistance to trastuzumab. GDF15, a distant member of the TGF-beta superfamily, has been associated with increased disease aggression in many malignancies. Our previous study showed that GDF15 activates the TGF-β receptor/src/HER2 signaling pathway, resulting in trastuzumab resistance. We recently observed that overexpression of GDF15 resulted in increased invasion in ovarian and breast cancer cells. In the present study, we investigate the molecular mechanisms underlying GDF15-induced invasion of HER2-overexpressing breast cancer cells resistant to trastuzumab. We demonstrate that GDF15-mediated invasion of breast cancer cells involves increased p38 MAPK activity. HER2-overexpressing breast cancer cells stably transfected with GDF15 showed EMT, increased cellular invasion, phosphorylation of p38, and increased MMP-2 and MMP-9 transcript expression. Furthermore, pharmacologic or genetic inhibition of p38 MAPK decreased invasion of breast cancer cells and improved response to trastuzumab. Also, knockdown of GDF15 suppressed expression of the p38 target genes MMP-2 and MMP-9. Finally, immunohistochemical analysis of a breast tumor tissue array showed a significant correlation (p=0.0053) between HER2 status and p38 phosphorylation in GDF15-positive breast cancers, as well as significant associations between GDF15 and MMP-2 (p=0.0027) and phosphorylated p38 and MMP-2 (0.0066) in HER2-overexpressing breast cancers. Our findings indicate a novel role for GDF15-stimulated p38 signaling in trastuzumab resistance, invasion, and tumor growth of HER2-overexpressing breast cancers.
Citation Format: Jayashree P. Joshi, Zhengjia Chen, Rita Nahta. Growth differentiation factor 15 causes increased invasiveness and EMT in HER2-overexpressing breast cancer via activation of p38 MAPK. [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 889. doi:10.1158/1538-7445.AM2013-889
Abstract 908: Identification of novel dynamic biomarkers of FGFR inhibition by the FGFR1,2 and 3 selective inhibitor AZD4547.
Authors: Delpuech Oona , Rooney Claire , Mooney Lorraine , McEwen Robert , Fenton Sarah , Baker Dawn , Shaw Robert , Dry Jonathan , Kilgour Elaine , Smith Paul 
Published: August 2014

Abstract
AZD4547 is an orally bio-available, highly selective and potent small molecule inhibitor, ATP competitive inhibitor of FGF receptors 1, 2 and 3. To identify novel dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a gene expression profiling study was performed. Cell lines defined as sensitive or resistant to AZD4547 (n=10 for each class) were treated with AZD4547 or DMSO control for 2, 6 or 24 hours and processed for microarray analysis. Amongst those genes modulated by AZD4547, the MEK signature genes DUSP6 and ETV5, together with the MAPK pathway regulator SPRED1 were repressed on AZD4547 treatment across all sensitive cell lines over time, consistent with FGFR signalling through this pathway. Further in vivo validation using three FGFR sensitive/responsive xenograft models (SNU16, KMS11, KG1a) was performed. We observed time dependent repression (16h to 24h) of DUSP6, ETV5 and SPRED1 across all three xenograft models which was consistent with plasma exposure of AZD4547 in vivo. In addition, modulation of these transcript biomarkers corresponded with inhibition of phosphorylation of FGFR, FRS2 and ERK, supporting engagement of the FGFR signalling pathway. Taken together, these data identify novel dynamic biomarkers of FGFR inhibition in vivo.
Citation Format: Oona Delpuech, Claire Rooney, Lorraine Mooney, Robert McEwen, Sarah Fenton, Dawn Baker, Robert Shaw, Jonathan Dry, Elaine Kilgour, Paul Smith. Identification of novel dynamic biomarkers of FGFR inhibition by the FGFR1,2 and 3 selective inhibitor AZD4547. [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 908. doi:10.1158/1538-7445.AM2013-908
Abstract 912: Targeting HER family signaling in low HER2-expressing breast cancer: activity of the selective and equipotent EGFR, HER2 and HER3 signaling inhibitor, AZD8931, in models of low HER2-expressing disease.
Authors: Marshall Gayle , Ashton Susan , Speake Georgina , D'Cruz Celina , Grondine Michael , Trigwell Cath , Bigley Graham , Beran Garry , Lynaugh Katy , Klinowska Teresa C. 
Published: August 2014

Abstract
Effective therapies for women with low-HER2 expressing breast cancer remain a significant unmet clinical need. We have detected significant phosphorylated-HER and HER2:HER3 dimer expression in clinical breast cancer samples without HER2 amplification suggesting that HER signaling may play a role in these tumors. It is our hypothesis that ligand-driven signaling is the major route of HER family activation in the absence of HER2 amplification.
AZD8931 is an orally bioavailable and highly selective small molecule inhibitor of EGFR, HER2 and HER3 signaling, which shows greatest potency when HER signaling is ligand-driven(1). In a range of low HER2 breast cancer cell lines, AZD8931 inhibited heregulin-driven proliferation (GI50 range 0.05 to 0.38μM) HER2:HER3 signaling, HER3:PI3K interaction and downstream signaling. In vivo, twice-daily oral dosing of AZD8931 showed significant monotherapy anti-tumor efficacy in a xenograft model of low HER2 breast cancer (MDA-MB-175VII) at well-tolerated doses (90% TGI at 12.5 mg/kg/bid).
We further evaluated the activity of AZD8931 in combination with paclitaxel, a commonly used standard of care chemotherapy for patients with advanced breast cancer expressing low levels of HER2. Pre-clinically, the combination of AZD8931 with paclitaxel showed at least additive activity in vitro in a range of breast cell lines and additive efficacy in vivo in a BT474 (high HER2) xenograft model at well tolerated doses (AZD8931 12.5 mg/kg/bid TGI 63%; paclitaxel 7.5mg/kg/qw TGI 41%; combination TGI 95%). Combination work in the low HER2 xenograft model is ongoing.
These data demonstrate that AZD8931 inhibits ligand-driven HER family receptor activation, receptor dimerization, PI3K interaction and downstream signaling leading to anti-tumor activity in vivo. These data also support the potential clinical utility of AZD8931 for the therapeutic treatment of low HER2 expressing breast cancers in combination with paclitaxel.
1 Hickinson et al. Clin.Cancer Res (2010) 16:1159-69.
Citation Format: Gayle Marshall, Susan Ashton, Georgina Speake, Celina D'Cruz, Michael Grondine, Cath Trigwell, Graham Bigley, Garry Beran, Katy Lynaugh, Teresa C. Klinowska. Targeting HER family signaling in low HER2-expressing breast cancer: activity of the selective and equipotent EGFR, HER2 and HER3 signaling inhibitor, AZD8931, in models of low HER2-expressing disease. [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 912. doi:10.1158/1538-7445.AM2013-912