bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4575: Altered catalytic properties of a subset of Met cytoplasmic domain variants occurring in renal cell carcinoma
Authors: De Silva Dinuka , Lee Young , Roy Arpita , Bottaro Donald P. 
Published: July 2016

Abstract
TCGA provisional data of papillary renal cell carcinoma (PRCC) kidney cancer, a malignant hereditary cancer syndrome, reveals that 23% of patients (n = 161) have MET gene amplification and/or mRNA up-regulation (2-fold or greater; RNA-Seq V2) and 10% of patients possess MET mutations. The Met tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF). HGF stimulation induces Met protein autophosphorylation and consequently enhances epithelial cell motility, morphogenesis, and proliferation. Chronic and/or overstimulation of Met contributes to tumor growth and metastasis. We determined Km and Vmax for ATP binding to full-length Met protein isolated from the PRCC derived cell line ACHN, which possesses the MET mutation T992I (numbered per SWISSPROT accession P08581) in the juxtamembrane domain, and the clear cell RCC derived cell line Caki-1, which possesses the MET V1220I mutation in the kinase domain. Catalytic constants were determined using two-site immunoassays for total Met and phospho-Met. Both variants were associated with increased Vmax relative to wild type Met protein isolated from B5/589 breast epithelial cells. The observed increased catalytic activity of receptor variants may confer a higher overall rate of signaling at lower ATP concentrations, potentially contributing to enhanced tumor cell motility and proliferation in both papillary and clear cell RCC.
Citation Format: Dinuka De Silva, Young Lee, Arpita Roy, Donald P. Bottaro. Altered catalytic properties of a subset of Met cytoplasmic domain variants occurring in renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4575.
Abstract 4579: Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased cell signaling and tumor cell intravasation
Authors: Fennell Imani N. , Scarlett Kisha A. , Coke Christopher J. 
Published: July 2016

Abstract
G-protein-coupled receptor (GPCR) heterodimerization has emerged as a means by which new signaling entities can be created with respect to agonist binding. Preliminary data from our lab indicates that agonist-bound GPCR C-X-C Chemokine Receptor 4 (CXCR4) and agonist-bound cannabinoid receptor 2 (CB2R) interact at the cell membrane and that receptor interaction mitigates the effects of CXCL12-mediated CXCR4 signaling. RhoA, Rac1 and Cdc42 are small GTP-binding proteins of the Rho family that are activated downstream of CXCR4 signaling. The effects of RhoA, Rac1 and Cdc42 on the actin cytoskeleton have led to established roles for Rho proteins in cancer cell motility, metastasis and intravasation. Here we report the novel finding that CXCR4/CB2R heterodimerization decreases Rho signaling, resulting in decreased intravasation. To test the effect of receptor heterodimerization on RhoA, Rac1, and Cdc42 activation, PC3 cells were treated with the CXCR4 agonist SDF1α, the CB2R agonist AM1241 or with a combination of SDF1α and AM1241 for 1 minute. Cell lysates were collected and immunoprecipitation experiments were performed to detect RhoA, Rac1 and Cdc42. To test the effects of CXCR4/CB2R heterodimerization on intravsation, we performed a zymography assay for the detection of metalloproteinase-2 (MMP2) and metalloproteinase-9 (MMP9), which are commonly secreted by CXCR4 signaling. Immunopreciptation results indicated an increase in RhoA and Rac1 protein levels after 1 minute in PC3 cells compared to the untreated control. However, when treated with SDF1α and AM1241 for 1 minute, RhoA and Rac1 levels decreased compared to SDF1α independent treatment; there was no observable change in Cdc42 protein levels. The results from the zymography experiments demonstrated that co-treatment with SDF1α and AM1241, which induces CXCR4/CB2R heterodimerization, led to decreased MMP-2 and MMP-9 activity, as compared to the SDF1α-independent treatment. Preliminary results provide novel evidence that CXCR4 and CB2R heterodimerize at the cell membrane, which may result in decreased signaling through RhoA and Rac1, but not through Cdc42. Furthermore, CXCR4/CB2R heterodimerization results in decreased MMP activation, thus abrogating intravsation.
Citation Format: Imani N. Fennell, Kisha A. Scarlett, Christopher J. Coke. Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased cell signaling and tumor cell intravasation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4579.
Abstract 4584: Apoptosis-mediated AXL activation: Contribution to metastatic cancers
Authors: Zweemer Annelien , Meyer Aaron , Lauffenburger Douglas 
Published: July 2016

Abstract
AXL is a receptor tyrosine kinase that is widely expressed in a variety of cancers and is predictive of poor patient outcome. This receptor is an essential epithelial-to-mesenchymal transition-induced regulator of cancer metastasis and is related to the occurrence of treatment resistance. AXL activation requires both the lipid moiety phosphatidylserine (PtdSer) and the bridging protein ligand Gas6. PtdSer is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs specifically during apoptosis. For that reason, we aimed to identify if apoptotic cell debris is capable of activating AXL on cancer cells and how this would affect the metastatic capacity of these cells.
In a non-AXL expressing tumor cell line (HCC827) apoptosis was induced by means of UV-irradiation. We detected AXL activation of AXL-expressing MDA-MB-231 cells that were treated with HCC827 cell debris, suggesting that apoptotic debris of dying tumor cells is capable of activating AXL in surviving surrounding tumor cells. Next we determined the contribution of PtdSer-mediated AXL activation to the migration of MDA-MB-231 cells in a wound scratch assay. The addition of warfarin, which prevents autocrine Gas6 binding to PtdSer, decreased migration to a similar extent as the AXL inhibitor R428.
This study revealed that PtdSer-mediated AXL activation contributes to the migration properties of MDA-MB-231 cells. As we detected AXL activation upon addition of PtdSer-containing apoptotic cells debris, this suggests that the induction of apoptosis by cancer therapeutics might enhance the metastatic capacities of neighboring surviving tumor cells. This finding may broadly impact the oncology field given AXL's widespread expression among different types of cancers, and provides a rationale for the design of novel combination therapies for decreasing tumor metastasis.
Citation Format: Annelien Zweemer, Aaron Meyer, Douglas Lauffenburger. Apoptosis-mediated AXL activation: Contribution to metastatic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4584.
Abstract 4585: ROR1 sustains caveolae and RTK-mediated survival signaling as a scaffold of cavin-1 and CAV1 in lung cancer
Authors: Yamaguchi Tomoya , Lu Can , Ida Lisa , Yanagisawa Kiyoshi , Usukura Jiro , Cheng Jinglei , Hotta Naoe , Shimada Yukako , Isomura Hisanori , Suzuki Motoshi , Fujimoto Toyoshi , Takahashi Takashi 
Published: July 2016

Abstract
TTF-1/NKX2-1, a homeobox-containing transcription factor indispensable for lung morphogenesis, was previously identified by four independent groups including us, as a “lineage-survival” oncogene involved in the pathogenesis of lung adenocarcinoma. We have further shown that TTF-1/NKX2-1 induces expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn plays a “sustainer” role for EGFR-mediated signaling. Interestingly, ROR1 knockdown effectively overcame EGFR-TKI resistance-conferring, HGF-mediated bypass signaling through MET, suggesting that ROR1 sustains not only EGFR but also additional RTK signaling. However, the underlying mechanism remained rather elusive.
We report here an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. Caveolae are 50-100 nm invaginations of the plasma membrane that play various physiological roles, including function as a platform for insulin-induced signaling in adipose tissue. We found that ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane in a kinase-independent manner, thereby preventing the lysosomal degradation of CAV1, as well as consequential caveolae formation. Caveolae structures and prosurvival signaling towards AKT through multiple RTKs such as MET and IGF-IR are consequently sustained. The present findings thus provide mechanistic insight into how ROR1 inhibition can overcome EGFR-TKI resistance due to bypass signaling via diverse RTKs, which is currently a major clinical obstacle.
Inhibition of prosurvival signaling and proliferation of lung cancer cells could be recapitulated by knocking down cavin-1 or CAV1, but they are unlikely to be suitable molecular targets for NSCLC treatment due to their crucial physiological functions in various organs even at low expression levels. In this regard, it should be noted that ROR1 is considered to be an onco-embryonic antigen with tumor-specific expression in adults. Taken together, development of novel therapeutic means to inhibit the scaffold function of ROR1 and thereby attack the cancer's “Achilles heel” is thus anticipated to be an attractive approach for improved treatment of this devastating cancer.
Citation Format: Tomoya Yamaguchi, Can Lu, Lisa Ida, Kiyoshi Yanagisawa, Jiro Usukura, Jinglei Cheng, Naoe Hotta, Yukako Shimada, Hisanori Isomura, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi. ROR1 sustains caveolae and RTK-mediated survival signaling as a scaffold of cavin-1 and CAV1 in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4585.
Abstract 4590: Mechanism of PI3K activation by the HER3/ErbB3 receptor
Authors: Michael Nicole , Hopkins Michael , Jura Natalia 
Published: July 2016

Abstract
Human epidermal growth factor receptor 3 (HER3, also known as ErbB3) is a receptor tyrosine kinase that lacks catalytic activity but is essential for cellular homeostasis due to its ability to allosterically activate its heterodimeric partners, EGFR and HER2 (also known as HER1/ErbB1 and ErbB2, respectively). HER3 is an important therapeutic cancer target because the signaling emanating from HER3 heterodimers is critical for the progression and maintenance of several human epithelial malignancies. This is primarily due to the potent ability of HER3 to recruit and activate the phosphoinositide 3-kinase (PI3K). This ability has been attributed to the presence of multiple direct binding sites for PI3K located in the intracellular tail of HER3. The advantage of having multiple recruitment sites is unclear and our recent data show that they provide little advantage to the ability of HER3 to activate PI3K. In addition, we have identified an alternative mode by which HER3 can activate PI3K, demonstrating a complex mechanism by which HER3 phosphorylation is coupled to activation of PI3K/Akt signaling pathway. Our results have important implications for therapeutic targeting of a number of human cancers in which HER3/PI3K signaling axis is abnormally activated and contributes to disease progression.
Citation Format: Nicole Michael, Michael Hopkins, Natalia Jura. Mechanism of PI3K activation by the HER3/ErbB3 receptor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4590.
Abstract 4598: Androgen receptor acetylation at K618 by ARD1 is essential for dissociation from HSP90 in prostate tumorigenesis
Authors: DePaolo John S. , Wang Zehua , Guo Jianhui , Zhang Guanyi , Zhang Haitao , Zabaleta Jovanny , Liu Wanguo 
Published: July 2016

Abstract
Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for its activation in both hormone-sensitive and castration-resistant disease. We previously reported that ARD1 is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the target residue within AR and the roles and mechanisms of the acetylation event in prostate tumorigenesis remained unknown. Here we show that ARD1 interacts with the AR DNA-binding domain and acetylates AR at lysine 618 (K618) in vivo and in vitro. Inhibition of K618 acetylation by replacing lysine with arginine significantly reduces AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation. Constitutive acetylation at K618 by replacing lysine with glutamine reverses these effects. Mechanistically, ARD1 forms a complex with both AR and HSP90. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation-defective K618R mutant is unable to dissociate from HSP90 following ligand exposure, and HSP90-dissociated AR is acetylated. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy. Given that K618 is also present in AR variants, the significance of ARD1-dependent acetylation of AR variants for castration-resistant PCa will be discussed.
Citation Format: John S. DePaolo, Zehua Wang, Jianhui Guo, Guanyi Zhang, Haitao Zhang, Jovanny Zabaleta, Wanguo Liu. Androgen receptor acetylation at K618 by ARD1 is essential for dissociation from HSP90 in prostate tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4598.
Abstract 460: Diagnostic and prognostic value of expression of CCND1 splice variant cyclin D1b in papillary thyroid carcinoma
Authors: Jung Chan Kwon , Jeon Sora , Kim Yourha , Lee Ahwon , Park Gyeong Sin 
Published: July 2016

Abstract
Background: An active cyclin D1 isoform, cyclin D1b, arises as a result of a failure to splice the fourth intron of the CCND1 pre-mRNA transcript. The expression of cyclin D1b has been associated with tumorigenesis and tumor progression in many types of human cancer. However, no studies with cyclin D1b have yet been reported in the thyroid cancer.
Methods: We investigated the CCND1 rs9344 (cDNA 870) polymorphism by TaqMan SNP genotyping assay and expression profiles of mRNA and protein of full-length cyclin D1 (cyclin D1a) and cyclin D1b by quantative real-time PCR and immunohistochemistry in 286 thyroid tumors including 16 nodular hyperplasias, 33 follicular adenomas (FA), 179 papillary thyroid carcinomas (PTC), 32 follicular thyroid carcinomas (FTC), 5 poorly differentiated carcinomas (PDC), 4 anaplastic thyroid carcinomas (ATC), and 17 medullary thyroid carcinomas (MTC). The relationships between cyclin D1 expression levels and clinicopathological features were analyzed.
Results: The cyclinD1b mRNA expression level in all thyroid tumors was significantly higher in the AA and GA genotype groups compared with the GG genotype group (p&lt;0.001 and p = 0.006, respectively). The mRNA expression levels of cyclin D1b was significantly higher in PTCs when compared to benign or other malignant tumors (p&lt;0.001) while no significant difference in cyclin D1a mRNA expression was observed according to the genotypes or tumor types. PTCs showed similar expression levels of cyclin D1b mRNA regardless of histologic subtypes, even when compared with follicular variant. In immunohistochemistry analysis, cyclin D1b overexpression was observed in PTC, PDC, ATC, and MTC, but not in FA and FTC. Cytoplasmic overexpression of cyclin D1b was significantly associated with advanced tumor stage in all PTCs (p = 0.025). Nuclear overexpression of cyclin D1b was associated with an increased incidence of lymph node metastases (p = 0.014) in classic PTCs.
Conclusion: The A allele of the rs9344 polymorphism predisposes for cyclin D1b production in thyroid cancer. Cyclin D1b overexpression has a diagnostic biomarker utility to differentiate PTC from benign follicular nodules and may be functionally involved in the progression of the disease.
Citation Format: Chan Kwon Jung, Sora Jeon, Yourha Kim, Ahwon Lee, Gyeong Sin Park. Diagnostic and prognostic value of expression of CCND1 splice variant cyclin D1b in papillary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 460.
Abstract 4602: A83-01 inhibits TGF-β/Smad3 and Wnt/β-catenin-mediated EMT and tumor metastasis in HER2-overexpressing breast cancer cells
Authors: Wu Yanyuan , Trinh Tran , Sarkissyan Marianna , Dwabe Sami , Kim Juri , Farias-Eisner Robin , Vadgama Jay 
Published: July 2016

Abstract
Interactions between Wnt and TGF-β (Transforming growth factor-β) signaling pathways play a critical role in promoting EMT (Epithelial to Mesenchymal Transition) and tumor metastasis. We previously demonstrated that activation of Wnt3/β-catenin signaling pathway promoting EMT is an important mechanism leading to HER2-cells becoming resistant to trastuzumab. In this study, we used HER2-overexpressing breast cancer cells to investigate the interactions between TGF-β and Wnt/β-catenin pathways in regulation of EMT and promoting breast cancer cells invasion. Our data showed that phosphorylation of Smad3 at ser423/425 by TGF-β led to nuclear localization of Smad3 and upregulation of Twist protein expression in HER2-overexpressing breast cancer cells. Cells treated with TGF-β showed poor response to trastuzumab and exhibited EMT-like phenotype; decreased E-cadherin and increased N-cadherin expression. A small molecule inhibitor, A83-01 which inhibits phosphorylation of Smad3 repressed TGF-β-induced nuclear accumulation of Smad3 and Twist expression. The A83-01 also inhibited TGF-β-induced cell migration and invasion and enhanced anti-tumor activity of trastuzumab. The TGF-β/Smad3 induced EMT in HER2-cells was found to be concordant with activation of Wnt3/β-catenin pathway. Following TGF-β treatment, Chromatin immunoprecipitation identified occupancy of Twist at promoter region of Wnt3. This data suggests that Twist in response to TGF-β activated Wnt3 gene transcription in HER2-overexpressing breast cancer cells. Knock-down of Twist by shRNA down-regulated Wnt3 expression and inhibited TGF-β-induced nuclear accumulation of β-catenin. Subsequently, TGF-β-induced matrix metalloproteinases, MMP1, MMP7, MMP9, VEGF (Vascular endothelial growth factors) and activation of Wnt/β-catenin signaling were repressed by the shRNA treatment.
In summary, our data demonstrated for the first time that the TGF-β/Smad3 mediated Twist results in transcriptional upregulation of Wnt3/β-catenin pathway and promotes EMT and cell invasion. The data suggests that therapeutic targeting of Twist by A83-01 and similar small molecules could inhibit the interaction between TGF-β and Wnt pathways and prevent breast cancer progressing to EMT and metastases.
Citation Format: Yanyuan Wu, Tran Trinh, Marianna Sarkissyan, Sami Dwabe, Juri Kim, Robin Farias-Eisner, Jay Vadgama. A83-01 inhibits TGF-β/Smad3 and Wnt/β-catenin-mediated EMT and tumor metastasis in HER2-overexpressing breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4602.
Abstract 462: The role of Her2 overexpression in Middle Eastern papillary thyroid cancer
Authors: Siraj Abdul K. , Beg Shaham , Bu Rong , AlSobhi Saif , Al-Dayel Fouad , Al-Kuraya Khawla 
Published: July 2016

Abstract
Thyroid cancer is the second most common malignancy among females in Saudi Arabia accounting for 7.4% of all cancers and 10.6% of all female malignant cancer. Among different subtypes, papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer. Although the overall cancer related ten year survival rate for PTC has reached 90%, local, regional and distant metastasis does occur in 10% of cases. Therefore, in search for new therapeutic targets for PTC, we investigated the role of Her2 oncogene in PTC as this gene is known to be involved in other cancers such as breast cancer. The aim of this study was to determine the prevalence and prognostic role of Her2 overexpression in Middle Eastern papillary thyroid carcinoma by immunohistochemistry (IHC), Fluorescent In-Situ Hybridization (FISH) and clinical data. A tissue microarray (TMA) containing &gt;1000 PTC cases with follow-up data was used. TMA sections were analysed at protein and DNA level using IHC and FISH. FISH analyses were performed to look for the gain or amplifications in Her2 gene. IHC analysis showed Her2 overexpression in 19.7% of our cases of PTC. Elevated expression was almost exclusively 2+ (194 tumors) and only rarely 3+ (1 tumor). Interestingly, no amplification of Her2 gene was visualized by FISH. Only 3% of our cases showed mildly elevated HER2 gene copy numbers not reaching the threshold for amplification. HER2 overexpression and copy number gains were unrelated to tumor stage, metastasis, patient survival and other clinical and pathological parameters. Our results demonstrated that Her2 overexpression occurs at relevant frequency in papillary thyroid cancer and in the absence of gene amplification. Additionally, expression of Her2 seems to hold no clinical value as prognostic factor in PTC
Citation Format: Abdul K. Siraj, Shaham Beg, Rong Bu, Saif AlSobhi, Fouad Al-Dayel, Khawla Al-Kuraya. The role of Her2 overexpression in Middle Eastern papillary thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 462.