bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-45: VEGFR3 signaling facilitates mammary tumor cells to resist chemotherapy
Authors: Sharma Bhawna , Varney Michelle L. , Singh Rakesh K. 
Published: May 2015

Abstract
Breast cancer is a deadly disease which accounts for more than 40,000 deaths each year in United States. With the availability of various treatment options, side effects and resistance associated with them is also becoming a major concern for the treatment of breast cancer. How breast cancer cells evade chemotherapy still remains a vast area for research. In this study, we proposed that mammary tumor cells resist cell death via VEGFR3 signaling pathway. To test our hypothesis, we used doxorubicin and paclitaxel resistant murine mammary tumor cells (Cl66-Dox and Cl66-Pac) which have been developed in our laboratory. When implanted in female Balb/c mice they form more aggressive tumor than the parent cells (Cl66) from which they have been derived. We observed that these resistant cells have higher expression of VEGFR3 receptor than parent cells at mRNA level. Treatment with VEGFR3 kinase inhibitor, MAZ51, Cl-66Dox and Cl66-Pac cells showed 50% growth inhibition at 10uM dose, suggesting VEGFR3 receptor activation as one of the mechanism for resistance. Moreover, when implanted in mice, tumor formed by resistant cells responded well to MAZ51 treatment with slower tumor growth in comparison to control group consistent with our in vitro data. However, when we treated mice bearing resistant tumors first with chemotherapeutic drug, docetaxel followed by MAZ51, we observed a significant decrease in tumor growth and tumor weight, examined upon endpoint analysis. These results suggest that combination treatment is more effective in inhibiting drug-resistant tumors growth in comparison to drug and inhibitor alone as determined by reduced tumor volume and weight in combination treatment group. Overall, our in vivo data showed that blocking VEGFR3 signaling pathway makes drug-resistant mammary tumor cells susceptible to chemotherapy suggesting the use of inhibitors for this signaling pathway to be beneficial for drug-resistant mammary tumors.
Citation Format: Bhawna Sharma, Michelle L. Varney, Rakesh K. Singh. VEGFR3 signaling facilitates mammary tumor cells to resist chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-45. doi:10.1158/1538-7445.AM2014-LB-45
Abstract LB-47: Specific and potent silencing of K-Ras by asymmetric RNA technology reveals addiction of gastric cancer stem cells
Authors: Sun Xiangao , Li Youzhi , Umehara Hiroki , Oishi Jun , Jesuraj Nithya , Barbulovic Jelena , Dai Xiaoshu , Gada Keyur , Li Chiang 
Published: May 2015

Abstract
The protein K-Ras is a molecular switch that under normal conditions regulates cell growth and cell division. Mutations in this protein lead to the formation of tumors through continuous cell growth. About 30% of human cancers have a mutated Ras protein that is constitutively bound to GTP due to decreased GTPase activity and insensitivity to GAP action. Ras is also an important factor in many cancers in which it is not mutated but rather functionally activated through inappropriate activity of other signal transduction elements. Mutated K-Ras proteins are found in a large proportion of all tumour cells. K-Ras protein occupies a central position of interest. The identification of oncogenically mutated K-Ras in many human cancers led to major efforts to target this constitutively activated protein as a rational and selective treatment. Despite decades of active agent research, significant challenges still remain to develop therapeutic inhibitors of K-Ras.
To elucidate the function of K-Ras in the cancer development and maintenance, we developed asymmetric interfering RNAs (aiRNAs) which are able to silence target genes with high potency leading to long-lasting knockdown, and reducing off-target effects, and investigated the dependency of K-ras on cell survival in several types of human cancer cell lines. Much to our surprise, we found K-Ras plays a more significant role for gastric cancer maintenance compared to other types of cancer. Here we report aiRNA-induced silencing of K-Ras inhibited the cell proliferation of gastric cancer cells and the ability of gastric cancer cells to form colonies compared to other cancer types. Accumulating evidence has revealed that cancer stem cells (CSCs) are highly associated with prognosis, metastasis, and recurrence. To investigate the effect of K-Ras on CSCs, we tested the K-Ras gene silencing effects on an in vitro CSC culturing system. As a result, K-Ras inhibition decreased the colonies derived from gastric CSCs and altered the gene expression patterns of several genes involved in “stemness” compared to other cancer types. The results of these studies suggest that gastric cancer and gastric CSCs are affected by the K-Ras oncogene and that Kras aiRNAs are promising therapeutic candidates for the treatment of gastric cancer.
Citation Format: Xiangao Sun, Youzhi Li, Hiroki Umehara, Jun Oishi, Nithya Jesuraj, Jelena Barbulovic, Xiaoshu Dai, Keyur Gada, Chiang Li. Specific and potent silencing of K-Ras by asymmetric RNA technology reveals addiction of gastric cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-47. doi:10.1158/1538-7445.AM2014-LB-47
Abstract LB-52: CBX7 inhibits breast cancer stem cell activity and tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway
Authors: Kim Hey-Yon , Park Ji-Hye , Won Hee-Young , Lee Jeong-Yeon , Kong Gu 
Published: May 2015

Abstract
Chromoprotein homologue 7 (CBX7), a member of the polycomb repressive complex (PRC)-1, has been involved in several biological processes including stem cell regulation and cancer development, but its roles in cancer stem cells (CSCs) and breast tumorigenicity remain unknown. Here, we demonstrated that CBX7 negatively regulates breast CSCs. CD44+/CD24-/ESA+ cells, a population of breast CSCs, showed diminished CBX7 expression compared with non-CSCs. Furthermore, small hairpin RNA (shRNA)-mediated CBX7 knockdown in breast epithelial and cancer cell lines increased breast CSC population and reinforced in vitro self-renewal and in vivo tumor initiating ability. Similarly, CBX7 overexpression showed reduced stemness of breast CSCs. We also found that CBX7 inhibits the Wnt/β-catenin/TCF pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist, to impede self-renewal of breast CSCs. Particularly, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of DKK-1 promoter. Furthermore, pharmacological inhibition of DKK-1 in CBX7 overexpressing cells showed recovery of the Wnt signaling and consequent rescue of breast CSC activity. Taken together, these findings indicated that CBX7-mediated epigenetic induction of DKK-1 is crucial for inhibition of breast CSC activity, suggesting that CBX7 could be a potential tumor suppressor as a novel negative regulator of CSCs in human breast cancer.
Citation Format: Hey-Yon Kim, Ji-Hye Park, Hee-Young Won, Jeong-Yeon Lee, Gu Kong. CBX7 inhibits breast cancer stem cell activity and tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-52. doi:10.1158/1538-7445.AM2014-LB-52
Abstract LB-54: HOXB7 regulates breast cancer stem cells via induction of TGFβ2
Authors: Liu Shou , Johnson Sarah , Chen Hexin 
Published: May 2015

Abstract
HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. HOXB7 is overexpressed in more than 70% of breast cancers. Overexpression of HOXB7 in breast epithelial cells and induces epithelial-mesenchymal transition. In this study, we found that overexpression of the HOXB7 gene in breast cell lines increases cancer stem cell populations and promotes cell invasion, in contrast, knockdown of HOXB7 expression decreases the proportions of cancer stem cells. Colonogenic assay and xenograft transplantation experiments further confirmed that overexpression of HOXB7 in breast cancer cells increases their tumorigenecity both in vitro and in vivo. Mechanistically we found that HOXB7 strongly induces TGFβ2 expression and activates the canonical TGFβ/SMAD signaling pathways, which may be responsible for induction of EMT leading to expansion of cancer stem cell population. Overall, our results suggest that HOXB7 may be a critical factor which regulates the self-renewal and differentiation of breast cancer stem cells and therefore a potential therapeutic target in breast cancer.
Citation Format: Shou Liu, Sarah Johnson, Hexin Chen. HOXB7 regulates breast cancer stem cells via induction of TGFβ2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-54. doi:10.1158/1538-7445.AM2014-LB-54
Abstract LB-55: UTX epigenetically regulates epithelial-mesenchymal transition-associated breast cancer stem cell properties independently of EZH2
Authors: Choi Hee-Joo , Park Ji-Hye , Park Mi-Kyung , Lee Chang-Hoon , Lee Jeong-Yeon , Kong Gu 
Published: May 2015

Abstract
UTX is a histone H3 lysine 27 (H3K27) demethylase that can antagonize a histone methyltransferase EZH2. Although H3K27 trimethylation by EZH2 has been involved in cancer-related biological processes including tumorigenesis, invasion, and stemness, the role of UTX in cancer progression has not been identified yet. In this study, we demonstrated an EZH2-independent tumor suppressive function of UTX in breast cancer. We found that loss of UTX enhanced self-renewal and tumorigenicity of breast cancer stem cells (CSCs) and also promoted CSC-associated epithelial-mesenchymal transition (EMT) through upregulating EMT-transcription factors (EMT-TFs), Snail, ZEB1 and ZEB2. Moreover, UTX positively regulated E-cadherin, a key marker of EMT, via these EMT-TFs. Notably, we identified that UTX facilitated epigenetic silencing of EMT-TFs by cooperating with c-Myc and various epigenetic modulators independently of EZH2. In the promoter regions of EMT-TFs, the levels of histone H3K4 methylation and H3 acetylation were inhibited by UTX. We also found that UTX formed a transcriptional repressive complex with LSD1, HDAC1, and DNMT1 for recruiting them to the promoters of EMT-TFs, while loss of UTX led to recruitment of c-Myc and p300 transcriptional active complex to these promoters. These effects were dependent on c-Myc, as UTX knockdown-induced epigenetic alterations of EMT-TFs and breast cancer stemness were reversed by siRNA-mediated c-Myc repression. Taken together, these data indicated that UTX negatively regulates EMT-induced breast CSCs by epigenetically repressing EMT-TFs independently of H3K27 methylation, suggesting a novel tumor suppressive role of UTX in breast cancer.
Citation Format: Hee-Joo Choi, Ji-Hye Park, Mi-Kyung Park, Chang-Hoon Lee, Jeong-Yeon Lee, Gu Kong. UTX epigenetically regulates epithelial-mesenchymal transition-associated breast cancer stem cell properties independently of EZH2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-55. doi:10.1158/1538-7445.AM2014-LB-55
Abstract LB-66: NVP-BEZ235 and bevacizumab as therapy for glioblastoma
Authors: Netland Inger Anne , Førde Hilde , Sleire Linda , Skeie Bente S. , Enger Per Øyvind , Goplen Dorota 
Published: May 2015

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumour. Its dismal prognosis despite multimodal treatment comprising surgery, radiotherapy and chemotherapy, calls for new therapeutic strategies.
GBM is a highly vascularized cancer, with elevated expression levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. Bevacizumab is a humanized anti-VEGF monoclonal antibody in clinical use as an angiogenesis inhibitor. Although bevacizumab is approved for treatment of GBM, several studies now show that it does not prolong survival. In addition, it has been shown that bevacizumab treatment leads to increased invasion and upregulation of gene transcripts involved in phosphoinositol-3-kinase (PI3K) - pathways. NVP-BEZ235 is a dual PI3K/mTOR kinase inhibitor. Combining NVP-BEZ235 with bevacizumab may therefore target both the angiogenic and invasive phenotype of GBMs.In vitro, the U-87 glioma cell line showed a dose-dependent reduction in cell proliferation to doses of NVP-BEZ235 from 0 to 250nM, as shown by direct cell count, BrdU incorporation and MTS assay. Furthermore, this was accompanied by a dose-dependent reduction of phosphorylated Akt at Serine 473, while the total levels of Akt remained unchanged. An IC50 of 11nM NVP-BEZ235 for the tumour material implanted, was determined in vitro by MTS assay. In order to validate combination treatment of BEZ235 and Avastin in vivo, we utilized a clinically relevant patient-based GBM xenograft model in NOD/SCID mice that mimics both the invasive and angiogenic growth pattern of human GBMs. In total 40 mice were allocated to four groups that received combination treatment with Avastin/BEZ235, monotreatment with Avastin or BEZ235 and untreated controls. Tumor engraftment and growth was confirmed and monitored longitudinally with MRI. The study is ongoing, survival data including histopathological analysis will be presented.
Citation Format: Inger Anne Netland, Hilde Førde, Linda Sleire, Bente S. Skeie, Per Øyvind Enger, Dorota Goplen. NVP-BEZ235 and bevacizumab as therapy for glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-66. doi:10.1158/1538-7445.AM2014-LB-66
Abstract LB-68: MYCN-induced TRPM7 expression and channel activity occurs through a mechanism that involves ornithine decarboxylase
Authors: Koomoa Dana-Lynn T. , Lange Ingo 
Published: May 2015

Abstract
Neuroblastoma (NB) is an extra-cranial solid cancer in children. MYCN is a transcription factor that regulates the expression of genes that are involved in cell proliferation, growth, cell migration, etc. MYCN gene amplification is a prognostic indicator of poor outcome in NB. Recent studies have shown that intracellular free calcium regulates multiple steps involved in cell migration. Although significant advances have been made in understanding the role of calcium during migration, little has been achieved towards understanding its impact on the malignant progression of NB. Our results showed that MYCN gene amplification or over-expression of MYCN in NB cells increased TRPM7 expression, increased peak TRPM7 current, induced constitutive TRPM7 channel activity, enhanced calcium signaling, and promoted cell migration, implicating TRPM7 as a potential regulator of calcium signals that promote NB cell migration and invasion. Recent results suggest that MYCN may regulate TRPM7 expression through a process that involves ornithine decarboxylase (ODC), a rate limiting enzyme in the biosynthesis of polyamines, and a direct transcriptional target of MYCN. Treatment of NB cells with α-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, or transfection of ODC specific siRNA effectively decreased TRPM7 expression. This effect was attenuated by supplementing the culture media with spermidine, confirming that ODC may function downstream of MYCN to regulate TRPM7 expression. Interestingly, western blot analysis of NB cell lysates showed that MYCN induced the cleavage of the TRPM7 kinase domain, a post-translational modification that has been shown to increase TRPM7 currents and induce constitutive TRPM7 channel activity. Additionally, DFMO inhibited TRPM7 cleavage, an effect that was reversed by spermidine supplementation. Taken together, these results suggest that MYCN may regulate TRPM7 expression and channel activity through a mechanism that involves ODC-mediated polyamine biosynthesis.
Citation Format: Dana-Lynn T. Koomoa, Ingo Lange. MYCN-induced TRPM7 expression and channel activity occurs through a mechanism that involves ornithine decarboxylase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-68. doi:10.1158/1538-7445.AM2014-LB-68
Abstract LB-69: Rab11 mediated focal adhesion turnover in sarcoma cell migration
Authors: Kao Ling-Yi , Wu Yi-Che , Chao Wei-Ting 
Published: May 2015

Abstract
Cell migration is central for many physiological and pathological processes, including embryogenesis, tissue repair, inflammatory responses, and cancer metastasis. Focal adhesion (FA) turnover has been demonstrated to play important role in controlling cell migration. Recently, FA disassembly was shown to be regulated by endocytosis during cell migration. Rabs are GTPase proteins that participate in various cellular vesicle transports; however, whether Rab proteins play the role in mediating vesicle transport for FA formation is not clear. This study is examining whether Rab11 mediated endosome recycling regulates FA formation during cell migration. Rab11 Wild-type, dominant negative or shRNA were transfected into human HT1080 fibrosarcoma cells, the cell motility was determined by trans-well assay and random migration assay, the localization of Rab11 and focal adhesion molecules were monitored by confocal microscopy. Results showed the Rab11 dominant negative form or shRNA transfection inhibited chemoattractive cell migration, however, only the Rab11 shRNA transfection inhibited random cell migration. Rab11 was also found colocalized with recycled β1 integrin and focal adhesion kinase and affected focal adhesion formation. Taken together, the results suggested Rab11 affected cell migration by regulating FAK dynamics and the activity of Rab11 is required for external stimulation. The interaction of Rab11 with associated focal adhesion molecules will be further investigated.
Citation Format: Ling-Yi Kao, Yi-Che Wu, Wei-Ting Chao. Rab11 mediated focal adhesion turnover in sarcoma cell migration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-69. doi:10.1158/1538-7445.AM2014-LB-69
Abstract LB-79: PRC2 loss amplifies Ras-driven transcription and sensitizes cancers to bromodomain inhibitor-based combination therapies
Authors: Raedt Thomas D. , Beert Eline , Pasmant Eric , Luscan Armelle , Brems Hilde , Ortonne Nicolas , Helin Kristian , Mautner Victor , Kehrer-Sawatski Hildegard , Clapp Wade , Bradner James , Upadhyaya Meena , Vidaud Michel , Legius Eric , Cichowski Karen 
Published: May 2015

Abstract
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumor types. However, loss-of-function mutations in PRC2 components occur in a subset of hematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Our genomic, cellular, and mouse modeling data demonstrates that the polycomb group gene SUZ12 functions as tumor suppressor in PNS tumors, glioblastomas, and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein and its loss drives cancer by activating Ras. We show that SUZ12-loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription. Importantly however, SUZ12-inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1, and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
Citation Format: Thomas De Raedt, Eline Beert, Eric Pasmant, Armelle Luscan, Hilde Brems, Nicolas Ortonne, Kristian Helin, Victor Mautner, Hildegard Kehrer-Sawatski, Wade Clapp, James Bradner, Meena Upadhyaya, Michel Vidaud, Eric Legius, Karen Cichowski. PRC2 loss amplifies Ras-driven transcription and sensitizes cancers to bromodomain inhibitor-based combination therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-79. doi:10.1158/1538-7445.AM2014-LB-79
Abstract LB-84: Mutant p53 enhances the metastatic potential of ovarian cancer cells
Authors: Ahn Ji-Hye , Lee Jong-Gyu , Choi Jung-Hye 
Published: May 2015

Abstract
Missense-mutations of TP53 resulting in accumulation of mutant proteins are very frequent in human cancer including ovarian cancer. Aggressive ovarian cancer is characterized by a peritoneal metastasis which involves the adhesion, migration, and invasion of tumor cells to the peritoneal cavity. In the present study, we investigated the effect of p53 GOF mutation (p53R248) on the metastatic potential of human ovarian cancer cells. We found that forced overexpression of p53R248 significantly increased adhesion to mesothelial cell Met5A, migration, and invasion in p53-null SKOV-3 cells. Conversely, knockdown of mutant p53 using siRNA significantly compromised p53R248-induced cell adhesion, migration, and invasion. Microarray analysis revealed that several metastasis-related genes including integrins and S1PR1(Sphingosine-1-phosphate receptor 1), and certain signaling pathway including PI3K/AKT were markedly up-regulated in p53R248 transfectant SKOV-3R248 cells. Inhibition of PI3K/Akt signaling using specific inhibitor significantly attenuated p53R248-mediated mesothelial cell adhesion, migration, and invasion. These finding show for the first time that mutant p53R248 may exert gain-of-function activity to regulate metastasis-related gene expression and the PI3K/Akt singling pathway in ovarian cancer.
Citation Format: Ji-Hye Ahn, Jong-Gyu Lee, Jung-Hye Choi. Mutant p53 enhances the metastatic potential of ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-84. doi:10.1158/1538-7445.AM2014-LB-84