bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2235: miR-200c reduces P-gp mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colon cancer
Authors: Li Qi 
Published: August 2015

Abstract
MicroRNA-200c (miR-200c) recently emerged as an important regulator of tumorigenicity and cancer metastasis, however, its role in regulating multidrug resistance (MDR) remains unknown. In the current study, we found that the expression levels of miR-200c in recurred and metastatic colorectal cancers (CRC) were significantly lower, while the JNK2 expression was higher compared to primary tumors. We showed that in MDR CRC cells, miR-200c targeted the 3′UTR of JNK2 gene. Over-expression of miR-200c attenuated the levels of p-JNK, p-c-Jun, P-gp and MMP-2/-9, the downstream factors of JNK signaling pathway, resulting in increased sensitivity to chemotherapeutic drugs, which was accompanied by heightened apoptosis and decreased cell invasion and migration. Moreover, in an orthotopic MDR CRC mouse model, we demonstrated that over-expression of miR-200c effectively inhibited the tumor growth and metastasis. At last, in the tumor samples from locally advanced CRC patients with routine post-surgical chemotherapy, we observed an inverse correlation between the levels of mRNA expression of miR-200c and JNK2, ABCB1, MMP-9 thus predicting patient therapeutic outcomes. In summary, we found that miR-200c negatively regulated the expression of JNK2 gene and increased the sensitivity of MDR CRC cells to chemotherapeutic drugs, via inhibiting the JNK2/p-JNK/p-c-Jun/ABCB1 signaling. Restoration of miR-200c expression in MDR CRC may serve as a promising therapeutic approach in MDR induced metastasis.
Citation Format: Qi Li. miR-200c reduces P-gp mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colon 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 2235. doi:10.1158/1538-7445.AM2015-2235
Abstract 2243: Alterations in the binding of Meis proteins to HoxB13 or to DNA promote prostate cancer progression
Authors: Brechka Hannah J. , Isikbay Masis , Bhanvadia Raj , Vander Griend Donald 
Published: August 2015

Abstract
Intro: One of the first germline mutations shown to confer an increased risk of early-onset prostate cancer (PrCa) is found in the Meis-binding domain of Homeobox B13 (HoxB13). Neither the function of this mutation nor the role of Meis proteins in PrCa has been elucidated. Meis proteins normally function as Hox gene cofactors, and regulate proliferation and cell fate. We hypothesize that disruption in normal Meis binding, either to transcriptional cofactors or DNA elements, is sufficient to alter gene transcription and increase progression of PrCa.
Methods: Meis1/2 expression was used to stratify outcomes of men with Gleason 6/7 tumors in a retrospective bioinformatics analysis. Meis1/2 mRNA expression in cell lines was determined by qRT-PCR, and isoform distribution determined by TA-TOPO cloning. Cell number over time was determined for lines stably overexpressing Meis2E or A as compared to GFP in LNCaP and CWR-22Rv1.
Results: We found that men diagnosed with intermediate Gleason scores and low expression of Meis had a worse prognosis than men with high levels of Meis. We found lower Meis mRNA expression in PrCa cell lines as compared to normal prostate epithelial cells. We determined that a variety of Meis2 isoforms are expressed in both cancer and normal, and the aggressive PrCa cell line CWR22Rv1 had a higher level of Meis2 isoforms with abrogated DNA-binding homeodomains. LNCaP cells overexpressing Meis2A showed significantly lower cell number over five days than GFP or Meis2E expressing cells.
Conclusions: Full length Meis proteins may act as tumor suppressors while the homeodomain-less isoforms may act as oncogenes in the context of PrCa. This is innovative because we are the first to look at the role of Meis proteins in PrCa, and significant because it's linked to evidence involving mutations in HoxB13.
Citation Format: Hannah J. Brechka, Masis Isikbay, Raj Bhanvadia, Donald Vander Griend. Alterations in the binding of Meis proteins to HoxB13 or to DNA promote prostate cancer progression. [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 2243. doi:10.1158/1538-7445.AM2015-2243
Abstract 2249: TERT promoter mutation as poor prognosis marker in glioblastoma via sphere formation and self- renewal capacity
Authors: Lee Jae-Ho , Lee Hyunsu , Woo Seon Rang , Joo Kyeung-Min , Park KeonUk 
Published: August 2015

Abstract
Telomerase reverse transcriptase (TERT) activity was increased allowing the maintenance of telomere length in cancers. TERT promoter mutation has been reported in a variety of cancers, especially in glioblastoma (GBM) with high frequency. In present study, we screened TERT promoter mutation in 25 GBMs and analyzed the results with their respective genetic profile and its renewal capacity by in vitro sphere formation. TERT promoter mutation (C228T, C250T) was found in 16 of 25 GBMs (64.0%) and was associated with male (p &lt; 0.01). They showed inverse correlations with IDH1 and ATRX mutations and a positive correlation with EGFR amplification though it did not show significance. GBM with sphere formation harbored higher frequency of TERT promoter mutation (91.6%) than those without sphere formation (27.3%; p = 0.01), which suggest that TERT mutation promotes self-renewal capacity of GBM. GBM with TERT mutations showed a shorter survival than those without TERT mutation in univariate analysis (median, 83.6 vs. 123.8 weeks; p = 0.045). These results suggested that TERT promoter mutation affect poor prognosis of GBM via promoting self- renewal capacity.
Citation Format: Jae-Ho Lee, Hyunsu Lee, Seon Rang Woo, Kyeung-Min Joo, KeonUk Park. TERT promoter mutation as poor prognosis marker in glioblastoma via sphere formation and self- renewal capacity. [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 2249. doi:10.1158/1538-7445.AM2015-2249
Abstract 2258: Myc drives Pten/ p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2
Authors: Nowak Dawid G. , Cho Hyejin , Herzka Tali , Wang Victoria M.Y. , Senturk Serif , DeMarco Daniel V. , Ding David , Fellmann Christof , Beinortas Tumas , Kleinman David , Watrud Kaitlin , Chen Muhan , Wilkinson John E. , Castillo-Martin Mireia , Cordon-Cardo Carlos , Robinson Brian D. , Trotman Lloyd C. 
Published: August 2015

Abstract
The sporadic transition from indolent to metastatic disease is a hallmark of prostate cancer (PC) and frequently involves deletion of PTEN and TP53. We recently recapitulated metastasis of Pten/ Trp53-mutant PC in mouse using the RapidCaP system and surprisingly, we found that it is driven by Myc, rather than Akt activation.
Here, we show that cell-cell communication by Il6 drives this Akt-Myc switch through activation of the Akt-inactivating phosphatase Phlpp2. Primary cells revealed that loss of Pten/ Trp53 triggers secretion of the Il6 cytokine when these genes are deleted together, but not separately. Il6 then communicates a downstream program of Stat3-mediated Myc activation, which drives cell proliferation. Abrogation of Myc activity by Myc inhibition with the JQ1 bromodomain inhibitor, Myc-RNAi, and Myc-CRISPR/ Cas9 approaches inhibited proliferation. We validated these findings in vivo, where peak proliferation in Pten/ Trp53 mutant primary and metastatic PC did not correlate with activated Akt, but with Stat3/ Myc activation instead. Most notably, we found that Myc strongly activates the Akt phosphatase Phlpp2 in primary cells and RapidCaP metastasis, and showed genetically that Phlpp2 is essential for dictating proliferation and Myc-mediated suppression of Akt.
Collectively, our data reveal competition between two proto-oncogenes: Myc and Akt, which ensnarls the Phlpp2 gene to facilitate Myc-driven metastasis.
Citation Format: Dawid G. Nowak, Hyejin Cho, Tali Herzka, Victoria M.Y. Wang, Serif Senturk, Daniel V. DeMarco, David Ding, Christof Fellmann, Tumas Beinortas, David Kleinman, Kaitlin Watrud, Muhan Chen, John E. Wilkinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Brian D. Robinson, Lloyd C. Trotman. Myc drives Pten/ p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2. [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 2258. doi:10.1158/1538-7445.AM2015-2258
Abstract 2260: Defining molecular mechanisms linking Endophilin A2 to metastasis in human breast cancer models
Authors: Baldassarre Tomas , Watt Kathleen , Truesdell Peter , Schneider Mark , Sengupta Sandip , Craig Andrew WB 
Published: August 2015

Abstract
Breast cancers in the human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) subtypes have high rates of tumor metastasis. Tumor metastasis is driven by formation of invadopodia that degrade extracellular matrix (ECM) in basement membranes to spread locally and colonize distant sites. Endophilin A2 (Endo II) is an adaptor protein that coordinates internalization and trafficking of receptors that drive invadopodia formation and breast cancer metastasis. We have recently identified Endo II as a positive regulator of human TNBC metastasis, invadopodia formation, epidermal growth factor receptor (EGFR) internalization and signaling. Here, we extend these studies of Endo II to HER2 breast cancers, and define molecular mechanisms that link Endo II to invadopodia formation and cell invasion. Analysis of Endo II expression in human invasive ductal carcinomas revealed significantly high expression of Endo II in HER2 primary tumors, and significantly higher expression in paired lymph node metastases compared to other subtypes. We also observed that high levels of Endo II mRNA was associated with reduced rates of relapse free survival in patients with lymph node positive, estrogen receptor negative tumors. This correlates with our findings that Endo II promotes invadopodia formation and breast cancer cell invasion. Mechanistically, these defects may be due to reduced EGFR signaling and lowered expression of epithelial-mesenchymal transition (EMT) signature genes observed in Endo II knock-down (KD) cells. We are currently validating these results in mammary orthotopic tumor xenograft models of HER2 and TNBC cell models with stable Endo II KD. Together, these findings identify high levels of Endo II in high risk breast cancer subtypes, with high expression of EMT genes, and a potential link between Endo II levels and poor prognosis in breast cancer patients.
Citation Format: Tomas Baldassarre, Kathleen Watt, Peter Truesdell, Mark Schneider, Sandip Sengupta, Andrew WB Craig. Defining molecular mechanisms linking Endophilin A2 to metastasis in human breast cancer models. [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 2260. doi:10.1158/1538-7445.AM2015-2260
Abstract 2266: CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling
Authors: Liu Bingya , Zang Ming-de , Li Jian-fang , Su Li-ping , Zhu Zheng-gang , Yan Min 
Published: August 2015

Abstract
CEACAM6 is a glycosylphosphatidylinositol (GPI)-linked immunoglobulin superfamily member that is implicated in a variety of human cancers. In our previous study, we reported that CEACAM6 was overexpressed in gastric cancer (GC) tissues and promoted cancer metastasis. The purpose of this study is to determine the role of CEACAM6 in tumor angiogenesis and vasculogenic mimicry (VM). We found that overexpression of CEACAM6 promoted tubular formation of human umbilical vein endothelial cells (HUVECs) and VM formation in GC. While opposing results were achieved in CEACAM6 knock-down groups. Interestingly, we found that mosaic vessels formed by HUVECs and GCs were observed in vitro by 3D-culture. Moreover, overexpression of CEACAM6 in GCs promoted tumor growth, VEGF secretion and VM structures in vivo. In accordance with these observations, we found that phosphorylation of FAK and phosphorylation of paxillin were up-regulated in CEACAM6-overexpressing GCs, and FAK inhibitor Y15 could reduce tube and VM formation. These findings suggest that CEACAM6 promotes tumor angiogenesis and VM may via FAK signaling, and CEACAM6 maybe a new potential target for cancer anti-vascular treatment.
Citation Format: Bingya Liu, Ming-de Zang, Jian-fang Li, Li-ping Su, Zheng-gang Zhu,Min Yan. CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling. [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 2266. doi:10.1158/1538-7445.AM2015-2266
Abstract 2267: Defining roles of SIN3 isoforms in breast cancer metastasis
Authors: Lewis Monica J. , Liu Jianzhong , Hurst Douglas R. 
Published: August 2015

Abstract
Metastasis continues to be the most difficult clinical challenge for breast cancer. These patients have unacceptable survival rates that have not changed in the past 20 years. Therefore, more effective therapeutic options are needed. The purpose of this study is to better understand molecular mechanisms of the SIN3 chromatin complexes that have been functionally associated with breast cancer progression to identify novel targeting strategies. Alteration of the composition of SIN3 complexes regulates the metastatic potential of breast cancer cells; and inhibition of SIN3 complexes induces differentiation and inhibits invasion of breast cancer cells. However, differences in the function of SIN3 isoforms (SIN3A and SIN3B) in breast cancer metastasis have not been characterized. To better define the role of SIN3 isoforms in breast cancer metastasis, we generated stable knockdown of SIN3 isoforms individually and in combination using 3 non-overlapping shRNA in two different metastatic breast cancer cell lines (MDA-MB-231 and -435). No significant change was noted in the proliferation rate of the transduced cells in vitro. Stable knockdown of SIN3B caused a significant decrease in invasion through Matrigel (28 ± 4 invaded cells/field compared to 50 ± 8 for control; p = 0.027) using a modified Boyden chamber that was corroborated by the decreased presence of stellate projections and a more epithelial phenotypic growth in 3D. Surprisingly, stable knockdown of SIN3A significantly increased invasion through Matrigel (98 ± 14 invaded cells/field; p = 0.008) and increased the presence of stellate projections in the 3D growth assay. Dual knockdown of SIN3A and SIN3B caused a significant decrease in invasiveness (19 ± 5 invaded cells/field; p = 0.003) and decreased presence of stellate projections similar to the phenotype noted with individual knockdown of SIN3B. These results were confirmed in vivo with an experimental metastasis assay (lateral tail vein injection in athymic nude mice) in which SIN3B knockdown significantly decreased lung metastasis (70% decrease compared to control; p = 0.009) and SIN3A knockdown increased metastasis (163% increase compared to control; p = 0.096). These results demonstrate key functional differences between SIN3 isoforms in regulating the process of metastasis. Our data suggests metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B that will be important in discovering novel therapeutic strategies for metastatic breast cancer patients.
Citation Format: Monica J. Lewis, Jianzhong Liu, Douglas R. Hurst. Defining roles of SIN3 isoforms in breast cancer metastasis. [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 2267. doi:10.1158/1538-7445.AM2015-2267
Abstract 227: Characterization of single cells from dissociated solid tumors
Authors: Middlebrook Aaron J. , Niknam Shahryar , Ruitenberg Joyce , Mach Albert J. , Suni Maria , Porter Warren , Hahn Friedrich , Snowden Eileen , Blaesius Rainer , Ghanekar Smita 
Published: August 2015

Abstract
The heterogeneous nature of solid tumors, coupled with the relatively small sample size of available biopsies, has led to an emerging need to glean as much information as possible from these valuable specimens. Current approaches to solid tumor analysis fail to completely reveal the diverse range of cellular compartments that comprise the tumor microenvironment. A comprehensive approach to tumor interrogation requires efficient tissue dissociation to facilitate analysis at the single-cell level. In contrast to current methods, single-cell analysis of tumor derived cell suspensions by flow cytometry has the potential to provide a more complete understanding of the many subpopulations within the tumor microenvironment and the cell to cell interactions that govern this space.
Here we demonstrate an efficient workflow that enables comprehensive single-cell analysis of solid tumors from breast cancers. Using tumors from clinical samples and mouse models, we evaluated different dissociation and processing techniques for their effects on cellular viability and surface marker expression. Solid tumors were dissociated into single-cell suspensions using a combination of mechanical dissociation and enzymatic digestion. Phenotypic distribution and morphology of cells within the tumor microenvironment was evaluated using flow cytometry. As this approach evolves, and a knowledge base of relevant surface markers is established, this technology has the potential to significantly impact how tumor biopsies are processed to get multiparametric information at a single cell level.
Citation Format: Aaron J. Middlebrook, Shahryar Niknam, Joyce Ruitenberg, Albert J. Mach, Maria Suni, Warren Porter, Friedrich Hahn, Eileen Snowden, Rainer Blaesius, Smita Ghanekar. Characterization of single cells from dissociated solid tumors. [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 227. doi:10.1158/1538-7445.AM2015-227
Abstract 2296: An isoform of BARD1, associated with many types of cancer, is a driver of oncogenesis by inducing telomere aberrations in vitro and in vivo
Authors: Pilyugin Maxim , Andre Pierre-Alain , Ratajska Magdalena , Irminger-Finger Irmgard 
Published: August 2015

Abstract
BARD1 has tumor suppressor functions by binding to BRCA1 and to p53 via RING finger and ankyrin repeats, respectively. The BARD1-BRCA1 heterodimer has E3 ligase activity, and the BARD1-p53 interaction promotes apoptosis. The expression of N-terminally truncated RING-less BARD1 isoforms, however, was correlated with poor prognosis in various cancers.
We performed overexpression experiments with various isoforms of BARD1 and found that BARD1δ, lacking RING and ANK regions, induces cell cycle arrest, multipolar mitotic spindles, genomic instability, and telomere aberrations. Co-localization studies and interaction assays in HeLa, MCF7, or HEK 293 cells, using tagged BARD1δ and full length (FL) BARD1, showed that the BRCT domains, present in BARD1δ and FL BARD1, interact with centrosome binding proteins and telomere binding proteins. BARD1δ overexpressing cells showed multipolar spindles and telomere alterations. Similar telomere alterations were observed in cells with reduced expression of FL BARD1 by siRNA. This is consistent with the observed distinct telomeric abnormalities in blood cells of patients with a BARD1 germline mutation that causes translation of a truncated protein lacking the BRCT domains. CRE-inducible BARD1δ transgenic mice showed dose-dependent growth arrest and tumor formation in various organs. These in vitro and in vivo observations suggest that BARD1δ plays a significant role in tumorigenesis by inducing genomic and telomere instability.
Citation Format: Maxim Pilyugin, Pierre-Alain Andre, Magdalena Ratajska, Irmgard Irminger-Finger. An isoform of BARD1, associated with many types of cancer, is a driver of oncogenesis by inducing telomere aberrations 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 2296. doi:10.1158/1538-7445.AM2015-2296
Abstract 2299: Generation and characterization of inducible KIF5B-RET mouse model of non-small cell lung cancer
Authors: Huang Qingling , Schneeberger Valentina E. , Luetteke Noreen , Jin Chengliu , Coppola Domenico , Wu Jie 
Published: August 2015

Abstract
The new precision oncology requires identification of driver oncogenes, validation of oncogene addiction, and development of oncogene-targeted drugs. Lung cancer is molecularly heterogeneous characterized by various genetic alterations, many of them occur at low frequencies. Recurrent RET fusion genes have been found in 1-2% of non-small cell lung cancer (NSCLC). Among them KIF5B-RET fusion is the most prevalent and occurs specifically in NSCLC. To develop an in vivo animal model for evaluation of KIF5B-RET fusion in lung adenocarcinoma, we generated transgenic mice containing a doxycycline (Dox)-inducible tetO-KIF5B-RET transgene. To express KIF5B-RET in lung type II epithelial cells, tetO-KIF5B-RET mice were crossed with CCSP-rtTA mice. CCSP-rtT/tetO-KIF5B-RET bitransgenic mice were induced with Dox and lung tissues were analyzed. KIF5B-RET mRNA and protein were detected in the lungs of Dox-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice. Histological examinations showed lung hyperproliferative lesions and tumors in Dox-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice. Thus, KIF5B-RET fusion is a driver oncogene sufficient to induce lung tumors in transgenic mice.
Citation Format: Qingling Huang, Valentina E. Schneeberger, Noreen Luetteke, Chengliu Jin, Domenico Coppola, Jie Wu. Generation and characterization of inducible KIF5B-RET mouse model of non-small cell lung 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 2299. doi:10.1158/1538-7445.AM2015-2299