bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 909: Mechanistic study of synergistic interaction between genistein and equol in MCF-7 human breast cancer cells in vitro
Authors: ONO MISAKI , EJIMA KAORU , TAKESHIMA MIKAKO , HIGUCHI TAKAKO , WAKIMOTO REI , NAKANO SHUJI 
Published: August 2015

Abstract
Soy isoflavones, such as genistein, daidzein, glycitein and equol, a metabolite of daidzein, have been suggested to affect the growth of estrogen-receptor positive breast cancer cells in vitro, and thus considered to be involved in the prevention of breast cancer. We have recently reported that soy isoflavone component mixture has a greater preventive activity against breast cancer rather than genistein alone using chemically induced rat model of hormone-dependent mammary carcinoma. Therefore, we investigated here whether a synergistic interaction exists between genistein and other isoflavone components in estrogen receptor positive MCF-7 cells. Effects of genistein in combination with other isoflavone components on proliferation, apoptosis, cell cycle perturbation, and signal proteins for survival, proliferation, and apoptosis were evaluated by WST-1 assay, FACS analyses, and Western blotting. Synergistic anti-proliferative activity of genistein was observed in combination with three respective isoflavone components, with the most efficacious interaction observed in combination with equal. In FACS study, cells were arrested at the G2/M by genistein but G1/S by equol. However, when these components were combined, cells were arrested at the G2/M, indicating a dominant effect of genistein over equol. Although apoptosis was not evident when cells were treated with either genistein or equol alone, combination treatment markedly induced apoptosis, with demonstrable cleavage of PARP. Upon combination treatment, constitutive activities of Erk1/2 were enhanced, but those of Akt were significantly inhibited, with subsequent reductions of activities of downstream mTOR. Reduced expression of anti-apoptotic Bcl-xL and enhanced expression of proapoptotic Bax were also demonstrated. These data indicate that synergic mechanism of genistein in combination with equol would be mediated by enhanced apoptosis induction through inactivation of Akt and its downstream molecule mTOR, followed by subsequent upregulation of Bax and downregulation of Bcl-xL, thus providing mechanistic rationale for soy isoflavone for the prevention of human breast cancer.
Citation Format: MISAKI ONO, KAORU EJIMA, MIKAKO TAKESHIMA, TAKAKO HIGUCHI, REI WAKIMOTO, SHUJI NAKANO. Mechanistic study of synergistic interaction between genistein and equol in MCF-7 human breast cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 909. doi:10.1158/1538-7445.AM2015-909
Abstract 912: Sulforaphane suppresses the growth of triple-negative breast cancer stem-like cells in vitro and in vivo
Authors: Castro Nadia P. , Rangel Cristina M. , Salomon David , Saylor Karen , Kim Young S. 
Published: August 2015

Abstract
Approximately 10-20% of breast cancer consists of triple-negative tumors, which present the poorest prognosis among the different subtypes. The triple-negative breast cancer (TNBC) tumors are known to be enriched with stem-like cells that are resistant to standard targeted drugs. Thus, it is extremely important to develop new agents that are non-toxic and specifically efficacious against these cancer stem-like cells (CSCs) that are suggested to be responsible for the initiation and maintenance of tumors. Here, we show that sulforaphane (SFN), a dietary component abundant in broccoli and broccoli sprouts, inhibits cell proliferation and sphere formation of the CSC population in TNBC cells.
TNBC stem-like cells were isolated from MDA-MB-231 Luci D3H1human triple negative breast cancer cells using fluorescently activated cell sorting (FACS) analysis. Six week old BalbC/nude mice were purchased from Jackson laboratory and fed with an AIN-96G-purified diet containing no SFN (Harlan Teklad Inc) until the end of experiments. The mice (n = 40) were treated with or without daily i.p. injection of 50mg SFN/kg b.w. for 2 weeks prior to the inoculation with MDA-MB-231 Luci D3H1 cells. The tumor cells were planted into both sides of the 4th inguinal mammary fat pads. The SFN treatment was continued for 3 additional weeks after the tumor cell xenografts.
Our results revealed that the CSC population isolated with CD49f+, CD24-/CD44high showed the ability to form mammoshperes, which is a characteristic of stemness. When these cells were treated with natural dietary constituent SFN at the concentration of 7.5 μM, they lost the property of mammosphere formation in vitro. Furthermore, SFN pre-treated animals (n = 20) exhibited a thirty percent reduction in tumor volume compared with control (saline 0.9%) at day 30 after the tumor cell inoculation. These data indicate that SFN suppresses triple negative mammary tumor formation both in vitro (7.5uM) and in vivo (50mg/kg bw) by targeting a CSC population. Further analysis on gene expression and protein profiles are being performed to elucidate whether stem-related developmental signaling pathways are being modulated by SFN.
Citation Format: Nadia P. Castro, Cristina M. Rangel, David Salomon, Karen Saylor, Young S. Kim. Sulforaphane suppresses the growth of triple-negative breast cancer stem-like cells in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2015-912
Abstract 920: Mechanism of the transferrin receptor 1 dysregulation in hepatocarcinogenesis
Authors: Kindrat Iryna , Tryndyak Volodymyr , de Conti Aline , Shpyleva Svitlana , Erstenyuk Anna , Beland Frederick A. , Pogribny Igor 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent life-threatening human cancers, with a rapidly increasing incidence worldwide. The pathogenesis of HCC is complex and consists of multiple interconnected molecular alterations. Current evidence indicates that altered iron metabolism plays an important role in the development and progression of HCC; however, there is a lack of conclusive information regarding the mechanisms of this dysregulation. In previous studies using different models of rodent carcinogenesis, we demonstrated prominent alterations of intracellular iron metabolism in preneoplastic livers, including changes in gene expression and the level of related proteins involved in the regulation of intracellular hepatic iron metabolism, primarily up-regulation of transferrin receptor 1 (TFRC). In the present study, we investigated the role and underlying mechanisms of the aberrant expression of TFRC, the main receptor controlling cellular iron uptake, in liver carcinogenesis. In both preneoplastic liver tissue from a relevant rat model of human HCC and in human HCC cells, there was a significant increase in the levels of TFRC mRNA and protein. This resulted in a substantial increase in TFRC/ferroportin (FPN) ratio, favoring an accumulation of iron in the HCC cells. The increase in levels of TFRC was attributed to a post-transcriptional microRNA-mediated mechanism. This was demonstrated by a computational analysis and confirmed experimentally by in vitro transfection experiments showing that transfection of human HCC cell lines with has-miR-152 effectively suppressed the expression of TFRC. Additionally, there was a strong inverse correlation between the level of TRFC and the expression of miR-152 in human HCC cells (r = -0.99, p = 4.7×10-9). Finally, the expression of TFRC and miR-152 in human HCC tissues was evaluated using the TCGA database. We observed an over-expression of TFRC in human HCC tissue samples and a markedly decreased level of miR-152 when compared to non-tumor liver tissue. These results demonstrate that dysregulation of cellular iron metabolism in liver carcinogenesis is driven by an up-regulation of TFRC, and indicate that miR-152-specific targeting of TFRC to decrease its levels may provide a selective anticancer therapeutic approach for the treatment of HCC.
Citation Format: Iryna Kindrat, Volodymyr Tryndyak, Aline de Conti, Svitlana Shpyleva, Anna Erstenyuk, Frederick A. Beland, Igor Pogribny. Mechanism of the transferrin receptor 1 dysregulation in hepatocarcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 920. doi:10.1158/1538-7445.AM2015-920
Abstract 922: Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer
Authors: Yang Shouhui , He Peijun , Wang Jian , Schetter Aaron , Tang Wei , Funamizu Naotake , Gaedcke Jochen , Ghadimi Michael , Gaida Matthias , Ried Thomas , Hannah Nader , Alexander H. Richard , Hussain S. Perwez 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Aberrant macrophage migration inhibitory factor (MIF) expression is associated with disease aggressiveness and increased MIF in PDAC predicts poor patient survival. Here we show that MIF-induced disease aggressiveness and poor survival in PDAC involves the inhibition of the nuclear receptor subfamily group c member 2 (NR3C2). Tumors with aberrant high levels of MIF (MIF-high) showed an increased expression of mir-301b and a decrease in NR3C2 expression as compared to the tumors with a lower level of MIF (MIF-low) in PDAC cases and a negative correlation existed between MIF and NR3C2 expressions in these tumors. Furthermore, patients with an increase in mir-301b or decrease in NR3C2 expression had a significantly shorter survival than other patients. MIF overexpression and knockdown confirmed that MIF up-regulates miR-301b, which then binds to the 3′UTR of NR3C2 and markedly decreases its expression. Moreover, MIF-overexpressing orthotopic tumor xenografts showed an increase in mir-301b and a decrease in NR3C2 expressions. MIF-induced regulation of mir-301b and NR3C2 functionally involved the PI3Kinase/Akt pathway. Examination of the tumor suppressor mechanism of NR3C2 revealed that it inhibits proliferation, colony formation, migration and invasion, and enhances sensitivity to chemotherapeutic drug gemcitabine in pancreatic cancer cells. Furthermore, NR3C2 knock down enhanced epithelial-to-mesenchymal transition. These data identify a novel MIF-induced signaling pathway targeting NR3C2, leading to increased disease aggressiveness and poor outcome in PDAC. We identified a MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor of PDAC, NR3C2, involving miR-301b. The inhibition of NR3C2 enhanced disease aggressiveness and predicted to poor survival, as shown by our survival analysis. Therapies that target the MIF-miR-301b-NR3C2 axis may improve disease outcome in pancreatic cancer.
Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Jochen Gaedcke, Michael Ghadimi, Matthias Gaida, Thomas Ried, Nader Hannah, H. Richard Alexander, S. Perwez Hussain. Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 922. doi:10.1158/1538-7445.AM2015-922
Abstract 923: Nitric oxide signaling pathway as a pathogenic driver in pancreatic cancer
Authors: Wang Jian , He Peijun , Gaida Matthias M. , Yang Shouhui , Schetter Aaron , Gaedcke Jochen , Ghadimi Michael , Ried Thomas , Yfantis Harris G. , Lee Dong H. , Weiss Jonathan M. , Hanna Nadar , Alexander H. Richard , Hussain S. Perwez 
Published: August 2015

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is among the most malignant cancers, with 5-year survival of 6%. Chronic inflammation is associated with increased risk of PDAC. Nitric oxide (NO) is an important mediator of inflammatory responses and plays a role in tumorigenesis. The principal source of an increased and sustained level of NO is inducible nitric oxide synthase (NOS2). In this study, we’ve tested the hypothesis that NO enhances tumor progression in pancreatic cancer. We found that higher NOS2 expression in tumors was associated with poor survival in resected PDAC patients (p = 0.011). We then investigated the role of NO by deleting NOS2 gene in a genetically engineered mouse model of pancreatic cancer (KPC mice) with pancreas-specific activation of mutant KRAS and P53, which faithfully recapitulates the development and progression of human pancreatic cancer. NOS2-deficient KPC mice showed longer survival compared to the KPC littermates with wildtype NOS2 (p&lt;0.01). Compared to tumors from KPC mice, KPC/NOS2−/− tumors were less vascularized (p&lt;0.001) and with less macrophage recruitment (p&lt;0.005), indicated by decreased expression of CD31 and F4/80 respectively. NOS2 deficiency led to attenuated proliferation and invasion, and enhanced apoptosis indicated by high level of cleaved caspase-3 (p = 0.02). Consistent with the less malignant phenotype, NOS2 deficiency reduced nuclear pERK accumulation (P = 0.034) and the subsequent phosphorylation of FOXO3 (p = 0.026). Further investigation showed a positive correlation between NOS2 expression and pFOXO level in human PDAC specimen (p = 0.005). In addition, NOS2 deficiency reduced the expression of a well known oncogenic microRNA, miR21 (p = 0.001). In summary, NOS2 gene expression in tumors is a candidate prognostic marker in resected pancreatic cancer patients, and NOS2/NO signaling may contribute to the pancreatic tumor progression by inactivating FOXO3 in KPC mice. In this ongoing study, we are further investigating the mechanistic role of NO in disease progression.
Citation Format: Jian Wang, Peijun He, Matthias M. Gaida, Shouhui Yang, Aaron Schetter, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Jonathan M. Weiss, Nadar Hanna, H. Richard Alexander, S. Perwez Hussain. Nitric oxide signaling pathway as a pathogenic driver in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 923. doi:10.1158/1538-7445.AM2015-923
Abstract 93: Universal homogenous bioluminescent assay that monitor the activity various classes of methyltransferases in vitro
Authors: Hsiao Kevin , Goueli Said 
Published: August 2015

Abstract
Post transcriptional modifications of proteins and nucleic acids are well-recognized to play major role in influencing cell fate towards cellular proliferation, differentiation, and cell death. Such modifications that include
phosphorylation, acetylation, methylation, etc. have been validated as drug targets resulting in the development of several drugs. Recent biochemical and biological data suggest that the enzymatic activities of several of these enzymes have pathogenic roles in cancer, inflammation, and neurodegenerative diseases. Thus, pharmacological modulation of these enzymes by small molecules will be beneficial in developing novel therapeutics for multiple unmet medical needs. Of these, methyltransferases are known to alter the epigenome by altering the methylation status of nucleic acids or proteins resulting in changes in cellular functions. Towards this goal of
searching for activators/inhibitors of these enzymes for the development of next generation of drugs, screening assays for these modulators are urgently needed. To address these unmet needs, we have developed a novel assay that monitors the activities of these enzymes and their modulation by small molecules. The assay is bioluminescent based, HTS formatted and highly sensitive. The assay is universal since it is based on monitoring the formation of the universal product S-adenosylhomocysteine (SAH), i.e., capable of detecting changes in activity of a broad range of methyltransferases such as DNA, protein, RNA, and small molecules methyltransferases. In addition, the assay has been validated for all classes of protein methyltransferases (Lysine and Arginine), and with different types of substrates (small peptides, large proteins, or even nucleosomes). This enables determining the specificity of these enzymes and their substrate requirements. The assay has high signal to background and low C.V. The assay is robust (Z’ value &gt; 0.7) and has been validated using various plate densities such as 96-, 384, and 1536-well plates. A strong feature of this assay is its utility with broad range of substrates with no limitations on the use of high concentrations of substrates or the composition of the substrates (short vs. long peptides), thus enabling the generation of kinetic data and determining the mechanism of action of various modulators of methyltransferases of interest.
Citation Format: Kevin Hsiao, Said Goueli. Universal homogenous bioluminescent assay that monitor the activity various classes of methyltransferases in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 93. doi:10.1158/1538-7445.AM2015-93
Abstract 940: Identification of Palbociclib response signature across indications
Authors: Zheng Xianxian , Ozeck Mark , Zhu Zhou , Ching Keith , Shields David , Hardwick James , Rejto Paul , VanArsdale Todd 
Published: August 2015

Abstract
Cellular proliferation is dependent on an orderly movement through the various phases of cell cycle. Progression through the G1 phase in particular requires phosphorylation of the retinoblastoma (Rb) protein which in turn releases E2F transcription factors resulting in transcriptional activation of response gene necessary for progression into S-phase. The cyclin D-CDK4/6 signaling pathway represent a critical regulatory pathway controlling transition from G1 into S-phase and greater than 90% of human tumors have mutations in this pathway. Palbociclib is a potent, selective, and orally bioavailable inhibitor of Cdk4/6. In human tumor xenograft models, Palbociclib has significant antitumor activities. The clinical activities of Palbociclib have also be demonstrated in the phase II PALOMA-1 trial for dramatic efficacy of postmenopausal patients with locally advanced or newly diagnosed estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer in combination with letrozole. To better understand the molecular mechanisms of Palbociclib response, we have identified a common set of gene signatures for ER+ BC as well as melanoma models. The physiological role of these genes regulated by Palbociclib is associated with DNA replication and repair, cell cycle, signal transduction, and Mitosis. Many of these genes have been previously identified as E2F signatures. In this study, we are aiming to expand this analysis to include two additional indications including Head and Neck squamous cell carcinoma (HNSCC) as well as squamous cell lung carcinoma (Sq lung) using Illumina RNASeq technology platform. Results from these studies will be presented and core Palbo-response signature will be discussed. In addition, we will also present the pharmacological effects of Letrozole on the gene expression changes for these core signatures in ER+ BC models.
Citation Format: Xianxian Zheng, Mark Ozeck, Zhou Zhu, Keith Ching, David Shields, James Hardwick, Paul Rejto, Todd VanArsdale. Identification of Palbociclib response signature across indications. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 940. doi:10.1158/1538-7445.AM2015-940
Abstract 948: A novel antibody-drug conjugate that induces long-term tumor regression and anticancer stem cell activity
Authors: Harper Jay W. , Lloyd Chris , Mao Shenlan , Lin Xin , Dimasi Nazzareno , Howard Phil , O'Connor Ellen , Farkas David , Barton Christopher , Smith Jeff , Zhong Helen , Chen Tracy , Hinrichs Mary Jane , Rebelatto Marlon , Yu Xiang-Qing , Spitz Susan , Pierce Andrew , Lai Dominic , Elaine Hurt , van Vlerken-Ysla Lilian , Sanjoo Jalla , Miller Katy , McCullough Karen , Kannan Priya , Thompson Simon , Mahadevia Parthiv , Martin Chris , Hollingsworth Robert , Kamal Adeela 
Published: August 2015

Abstract
Antibody-drug conjugates (ADCs) selectively deliver cytotoxic agents to tumors and provide the potential for increased clinical benefit to cancer patients. We have developed an ADC consisting of an antibody against a target expressed on the surface of tumor cells that is site-specifically conjugated with a pyrrolobenzodiazepine (PBD) dimer payload (PBD-ADC). The tumor-associated antigen is overexpressed in many carcinomas, on both bulk tumor cells and cancer stem cells (CSCs), while normal tissue expression is limited, thus making it an ideal ADC target. The PBD payload was selected due to its picomolar potency and because, unlike tubulin inhibitors, it could be cytotoxic to CSCs as well as bulk tumor cells. The PBD-ADC is significantly efficacious in target-positive in vivo tumor models of gastric, breast and lung carcinomas, inducing long-term tumor regressions and demonstrates greater potency compared to ADCs conjugated with either tubulysin or auristatin payloads, both tubulin inhibitors. Additionally, the PBD-ADC significantly reduced the CSC population of tumors in vivo, unlike ADCs bearing tubulin inhibitor payloads. The PBD-ADC appears to be efficacious against tumors that have acquired resistance to a tubulysin-based ADC, however possible mechanisms of resistance to this PBD-ADC are being investigated. Collectively, this novel ADC represents a promising therapy that may deliver durable clinical responses in indications with unmet medical need.
Citation Format: Jay W. Harper, Chris Lloyd, Shenlan Mao, Xin Lin, Nazzareno Dimasi, Phil Howard, Ellen O'Connor, David Farkas, Christopher Barton, Jeff Smith, Helen Zhong, Tracy Chen, Mary Jane Hinrichs, Marlon Rebelatto, Xiang-Qing Yu, Susan Spitz, Andrew Pierce, Dominic Lai, Hurt Elaine, Lilian van Vlerken-Ysla, Jalla Sanjoo, Katy Miller, Karen McCullough, Priya Kannan, Simon Thompson, Parthiv Mahadevia, Chris Martin, Robert Hollingsworth, Adeela Kamal. A novel antibody-drug conjugate that induces long-term tumor regression and anticancer stem cell activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2015-948