bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3137: Breast cancer anti-estrogen resistance 4 (BCAR4) is a novel oncogene in lung cancer
Authors: Bae Kieun , Lee Minkyong , Yoon Daseul , Kim Yun-Hee , Yoon Kyong-Ah 
Published: July 2017

Abstract
BCAR4 was identified as tamoxifen resistance related gene in breast cancer due to its function to activate estrogen-independent cell growth. Instead of estrogen receptor, ERBB2 and ERBB3 genes were activated by BCAR4 in tamoxifen resistant cells. Recently, the function of BCAR4 as a long non-coding RNA (lncRNA) was reported to regulate a non-canonical Hedgehog/GLI2 pathway in breast cancer. However, the association of BCAR4 and lung cancer has not been identified. Here, we describe the oncogenic effect of BCAR4 in human lung cancer. Expression pattern of BCAR4 was examined in lung cancer cell lines, primary tumor tissues, and adjacent normal tissues. BCAR4 was highly expressed in 71% of lung cancer cell lines and especially in 43% of cancer tissues of lung adenocarcinoma patients who did not harbor the activational mutations of EGFR nor KRAS. Exogenous expression of BCAR4 protein promoted cell growth of non-tumorigenic bronchial epithelial cell line, BEAS-2B, and lung cancer cell line, NCI-H1299. We also confirmed the oncogenic feature of BCAR4 by colony forming assay using stably expressing cells. These effects were notably reduced after knockdown of BCAR4 by small interfering RNA. BCAR4 encoded a functional protein and its overexpression resulted in the enhanced migration than controls cells. This result proposed a similar role of BCAR4 in lung cancer considering its previously reported role in breast cancer metastasis. We also detected a fusion gene of BCAR4 in a lung cancer tissue by analyzing RNA-sequencing data. BCAR4 protein as well as its fusion form showed the improved tumorigenic feature in the mouse xenograft model with lung cancer cells. We compared the gene expression pattern in BCAR4 overexpressed cells to identify the possible mechanism of the oncogenic effect of BCAR4. Cyclin D1, Cyclin E, and MMP1 mRNA and protein levels were significantly increased after BCAR4 overexpression. However, downstream genes of GLI2 signaling were not altered by protein expression of BCAR4 arguing an alternative role for lncRNA BCAR4. Our results suggest a novel oncogenic role of BCAR4 protein in lung cancer.
Citation Format: Kieun Bae, Minkyong Lee, Daseul Yoon, Yun-Hee Kim, Kyong-Ah Yoon. Breast cancer anti-estrogen resistance 4 (BCAR4) is a novel oncogene in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3137. doi:10.1158/1538-7445.AM2017-3137
Abstract 3140: MUC1 expression as a prognosis marker and a new therapeutic target in patient with duodenal adenocarcinoma
Authors: Shiba Satomi , Miki Atsushi , Ohzawa Hideyuki , Teratani Takumi , Sakuma Yasunaru , Kitayama Joji , Lefor Alan Kawarai , Sata Naohiro 
Published: July 2017

Abstract
Background: Mucin1 (MUC1) is a glycoprotein as a member of the mucin family. The expression has been associated with poor prognosis in patients with several types of cancer. Duodenal cancer is rare, therefore details are not known including carcinogenesis and clinical treatment. We verify the association of MUC1 expression and prognosis in patient with duodenal adenocarcinoma. We also assess the function of MUC1 in vitro. Materials and Methods: Between 1989 and 2014, eighteen patients of duodenal adenocarcinoma with surgery at Jichi Medical University Hospital were included in this study. MUC1 expression was evaluated immunohistochemically with anti-MUC1 antibody to examine the association of MUC1 expression and prognosis clinicopathologically. A human-derived duodenal cancer cell line, HuTu-80, is used for the experiments of invasiveness and proliferation in vitro. The invasive capacity was evaluated by transfection of siRNA into HuTu80 with matrigel invasion assay. Viability assay with the anti-MUC1 peptide GO201 was assessed to determine whether MUC1 associate with cell growth of duodenal adenocarcinoma. Results: Seven cases were MUC1 positive and 11 were MUC1 negative immunohistochemically. TMN staging was not associated with MUC1 expression. Kaplan-Meir analysis showed a poor prognosis with MUC1 positive patients in cumulative overall survivals (MUC1 positive : MUC1 negative, 18M : 52M; HR:20.6, 95%CI 3.247-130.7,p=0.002). Lymph node metastasis of MUC1 positive patients (71.4%) was significantly higher than MUC1 negative patients (9%) (p = 0.01). In vitro experiment, the expression of MUC1 was confirmed by RT-PCR and flowcytometry. Knockdown experiment with transduction of siRNAs to HuTu80 decreased the expression of the MUC1 gene. Transduction of siRNAs significantly reduced invasive capacity (47.02±21.65%, 95%CI 3.046-102.9, p= 0.04). Growth of HuTu80 cells was inhibited by GO201 (5 μM : 95%CI 0.109-0.3565, 10μM :95%CI 0.024-0.389 p&lt;0.0001). Conclusions: MUC1 expression is a predictive marker for poor prognosis in patients with duodenal adenocarcinoma. Functional Interference of MUC1 core protein reduces cell growth and invasiveness. Taken together, MUC1 is associated with malignant potential and a novel target for the treatment.
Citation Format: Satomi Shiba, Atsushi Miki, Hideyuki Ohzawa, Takumi Teratani, Yasunaru Sakuma, Joji Kitayama, Alan Kawarai Lefor, Naohiro Sata. MUC1 expression as a prognosis marker and a new therapeutic target in patient with duodenal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3140. doi:10.1158/1538-7445.AM2017-3140
Abstract 3146: Targeting ANXA3 in combination with sorafenib for the treatment of hepatocellular carcinoma
Authors: Tong Man , Luk Steve , Che Noelia , Ding Jin , Lee Terence KW , Ma Stephanie 
Published: July 2017

Abstract
Sorafenib is the only FDA-approved tyrosine kinase inhibitor for targeted therapy in advanced HCC. Nevertheless, its efficacy is limited with only a modest improvement in patient outcome, likely due to acquired resistance. In-depth understanding of the molecular mechanism of sorafenib resistance is warranted for the development of novel treatment strategies. Recent studies by us and others have characterized liver tumor-initiating cells (T-ICs) to be a possible source of resistant and recurrent tumors and a plausible target for HCC treatment. Our group has previously identified CD133 to be a functional marker of liver T-ICs and found annexin a3 (ANXA3) to regulate cancer and stem cell-like properties in this subset of cells. Interestingly, our recent observations also found CD133+ liver T-ICs to be more resistant to sorafenib. Sorafenib resistant clones, established in HepG2 and Huh7 cells by continuous exposure to increasing concentrations of sorafenib, displayed enhanced abilities to migrate, invade, self-renew, and initiate tumor formation in immunodeficient mice, as well as higher expression of stemness associated genes. These two sorafenib resistant cell lines and two other sorafenib resistant HCC patient-derived xenografts established in a similar manner were also found to be enriched for CD133 and ANXA3 expression. Sorafenib resistant clones with ANXA3 stably suppressed were re-sensitized to sorafenib treatment and had diminished ability to migrate, invade, self-renew and initiate tumor growth in vivo, further substantiating the role of ANXA3 in mediating sorafenib resistance in HCC. Mechanistically, an activated PKC/ERK/FRA2 signaling axis was found to be responsible for driving this phenomenon. Clinically, ANXA3 expression was also found to have prognostic value as a higher ANXA3 expression in HCC patients who have received sorafenib treatment was correlated with poor overall survival. The combinatorial use of a homemade ANXA3 neutralizing antibody and sorafenib on HCC patient derived xenografts is now being investigated as a potential new treatment regimen for combating sorafenib resistance in HCC.
Citation Format: Man Tong, Steve Luk, Noelia Che, Jin Ding, Terence KW Lee, Stephanie Ma. Targeting ANXA3 in combination with sorafenib for the treatment of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3146. doi:10.1158/1538-7445.AM2017-3146
Abstract 3156: Multiple acquired resistance mechanisms against third generation EGFR-TKI osimeritinib in non-smal cell lung cancer cells
Authors: Namba Kei , Shien Kazuhiko , Yoshioka Takahiro , Torigoe Hidejiro , Sato Hiroki , Yamamoto Hiromasa , Soh Junichi , Tsukuda Kazunori , Toyooka Shinichi 
Published: July 2017

Abstract
Background Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective against the EGFR-T790M variant, which is accounts for half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, resistance to osimertinib is likely to progress and the study of potential osimertinib-resistance mechanisms in advanced is necessary. In this study, we investigated the molecular and cellular profiles of the acquired resistance cells to osimertinib in EGFR-mutant non-small cell lung cancers. Materials and Methods Five EGFR-mutant cell lines were exposed to osimertinib by stepwise escalation or high-concentration exposure methods, and resistant sublines to osimertinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Results EGFR-C797S mutation which was reported to be a major mechanism of resistance to osimertinib in clinical samples was not detected in established resistance cells by using direct sequencing. Several osimertinib-resistance cell lines displayed MET amplification, and some of these cells were sensitive to the combination of osimertinib plus MET inhibitor crizotinib. However, one cell line that displayed MET amplification was not sensitive to this combination therapy. On the other hand, several osimertinib-resistance cell lines displayed epithelial-to-mesenchymal transition (EMT) features. The HCC827-derived subline established by the high-concentration exposure method exhibited not only EMT features but also cancer stem cell (CSC)-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) and ATP binding cassette subfamily B member 1 (ABCB1) overexpression. Conclusion We established osimertinib-resistant cells and found that MET amplification, EMT, and CSC -like features were observed. These findings may provide clues to overcome acquired resistance to EGFR-TKIs. In some cell lines, however, the mechanisms of acquired resistance to osimertinib were not revealed yet.
Citation Format: Kei Namba, Kazuhiko Shien, Takahiro Yoshioka, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka. Multiple acquired resistance mechanisms against third generation EGFR-TKI osimeritinib in non-smal cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3156. doi:10.1158/1538-7445.AM2017-3156
Abstract 3170: MCAM modulates small cell lung cancer chemoresistance via PI3k/Akt/Sox2 signaling pathway
Authors: Tripathi Satyendra C. , Fahrmann Johannes F. , Celiktas Muge , Aguilar Mitzi , Marini Kieren D. , Jolly Mohit K. , Katayama Hiroyuki , Wang Hong , Murage Eunice N. , Dennison Jennifer B. , Watkins D. Neil , Levine Herbert , Ostrin Edwin J. , Taguchi Ayumu , Hanash Samir M. 
Published: July 2017

Abstract
Despite favorable responses to initial therapy SCLC relapse occurs within a year exhibiting a multidrug resistant phenotype. Due to limited accessibility of patient tissues for research purpose, SCLC patient derived xenografts (PDXs) have provided the best opportunity to address this limitation. We sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines that exhibited a mesenchymal phenotype and in chemoresistant PDXs compared to matched treatment-naïve tumors. MCAM is a cell membrane protein whose expression has been implicated in multiple human cancers. MCAM expression is also detected in lung adenocarcinoma; however, its expression and role in SCLC is still not been explored. MCAM knockdown in chemoresistant cells reduced cell proliferation and decreased the IC50 inhibitory concentration of chemotherapeutic drugs. MCAM was found to modulate sensitivity of SCLC cells to chemotherapeutic drugs through up-regulation of MRP1/ABCC1 expression and of the PI3K/AKT pathway in a SOX2 dependent manner. Metabolomic profiling revealed that MCAM can modulate glutamic acid and lactate production in chemoresistant cells with a distinct metabolic phenotype sustaining low oxidative phosphorylation. MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.
Citation Format: Satyendra C. Tripathi, Johannes F. Fahrmann, Muge Celiktas, Mitzi Aguilar, Kieren D. Marini, Mohit K. Jolly, Hiroyuki Katayama, Hong Wang, Eunice N. Murage, Jennifer B. Dennison, D. Neil Watkins, Herbert Levine, Edwin J. Ostrin, Ayumu Taguchi, Samir M. Hanash. MCAM modulates small cell lung cancer chemoresistance via PI3k/Akt/Sox2 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3170. doi:10.1158/1538-7445.AM2017-3170
Abstract 3178: The p53 tumor suppressor protein paradoxically drives chemo-resistance in human medulloblastoma cells through suppressing the mTOR AKT pathway
Authors: Naeem Aisha , Choudhry Muhammad U. , Avantaggiati Maria L. , Rodriguez Olga C. , Albanese Chris 
Published: July 2017

Abstract
Medulloblastoma (MB) accounts for approximately 25% of childhood brain tumors with 70% of the cases occurring in children under 10. Prognosis for children less than three years old is considerably worse and, due to its destructive effects on the developing nervous system, irradiation is largely avoided in this age group. The p53 pathway is considered a key determinant of anti-tumor responses in many tumors; however, its role in the regulation of cell survival, chemo-sensitivity and chemo-resistance in MB is much less well defined. It has been shown that p53 pathway defects, mutations and nuclear levels increase significantly from MB diagnosis to relapse and correlate with an adverse prognosis. We recently reported on the highly novel and unexpected finding that both the genetic (sh-RNA) and chemical silencing of p53 led to a significant increase in cell death by the drug VMY in MB cell lines with elevated basal p53 (e.g. in D556 cells which express wild type p53 and in DAOY cells that contain mutant p53) as measured by colony forming assays, DNA degradation assays and annexin-V staining, suggesting a surprising commonality in the p53 signaling in both cell lines despite the differences in their p53 status. Equally surprising was the observation that the silencing of p53 in D556 cells enhanced cell death by the clinically used drugs doxorubicin and vincristine. Conversely, we now find that suppressing p53 with sh-RNA in D283 cells, which express much lower levels of wild type p53 compared to D556, resulted in the more classical chemoresistance profile, suggesting a form of p53 ‘addiction’ in D556 and DAOY cells. Mechanistically, we observed that suppressing p53 with sh-RNA in D556 cells treated with VMY or doxorubicin significantly increased the levels of phosphorylated Chk1, S6K, gH2AX, and MDM2. Importantly, phospho-mTOR levels were also significantly increased in the D556/p53 sh-RNA cells and the suppression of mTOR enhanced chemoresistance. These somewhat paradoxical findings suggest that activated Akt/mTOR may induce MB cell death and that suppression of mTOR by p53 enhances chemoresistance. Our data provide new mechanistic insights into the role of p53 in primitive neuroectodermal tumors and may provide new approaches for enhancing the clinical outcome of patients with MB.
Citation Format: Aisha Naeem, Muhammad U. Choudhry, Maria L. Avantaggiati, Olga C. Rodriguez, Chris Albanese. The p53 tumor suppressor protein paradoxically drives chemo-resistance in human medulloblastoma cells through suppressing the mTOR AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3178. doi:10.1158/1538-7445.AM2017-3178
Abstract 3184: Autophagy regulation by vacuolar-ATPases: A contributing mechanism of chemo-resistance in ovarian cancer
Authors: Kulshrestha Arpita , Katara Gajendra K. , Ibrahim Safaa A. , Gilman-Sachs Alice , Beaman Kenneth D. 
Published: July 2017

Abstract
In ovarian cancer (OVCA), the main obstacle in the clinical usefulness of platinum based drugs is the eventual emergence of chemo-resistant tumors. Exposure of cancer cells to platinum drugs such as cisplatin elicits a stress response that leads to the induction of coping mechanisms favoring cancer cell survival. Autophagy induction is the primary protective mechanism in cancer cells that also contributes to cisplatin resistance. A tightly regulated pH is imperative for autophagy and the role of major pH regulators is therefore vital to this process. Vacuolar ATPases (V-ATPases) are the multi-subunit proton pumps that regulate intra/extra-cellular pH in cancer. Its `a2` isoform (V-ATPase-a2) is located at the plasma membrane and early/late endosomal compartments. We previously found that this isoform is overexpressed on cisplatin resistant cells (cis-R) and its inhibition sensitizes cis-R cells to platinum drugs. In continuation with our efforts, the present study was performed to understand what alterations in the autophagy process occur upon V-ATPAse-a2 inhibition and how these contribute to cisplatin sensitization. Expression profiling of ovarian cancer cells lines (A2780-cis R and TOV-112D- cis R) revealed that upon a2 inhibition, the basal levels of autophagosome membrane protein, LC3B were enhanced compared to control cis-R cells as determined by flow cytometry and western blot analysis. Upon cisplatin treatment, the LC3B levels were further enhanced in a2 inhibited cis-R cells compared to control cells. Further, we observed a significantly increased expression of the autophagy protein, beclin-1 in these cells as compared to control cells. In addition, the inhibition of V-ATPase-a2v increased the protein levels of SQSTM1/p62, a known substrate for the autophagy process. The enhanced LC3B and P62 levels suggest an accumulation of the autophagosomes due to an altered autophagy flux upon V-ATPase-a2v inhibition. The study provides a rationale for the utility of V-ATPase-a2 inhibitors in combination with standard drugs as a novel strategy to improve the treatment efficacy of the chemoresistant ovarian cancer.
Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Safaa A. Ibrahim, Alice Gilman-Sachs, Kenneth D. Beaman. Autophagy regulation by vacuolar-ATPases: A contributing mechanism of chemo-resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3184. doi:10.1158/1538-7445.AM2017-3184
Abstract 3188: ER-stress induced translational regulation by RGS2 leads to tumor-promoting microenvironment and chemoresistance
Authors: Min Hye-Young , Park Shin-Hyung , Lee Ho Jin , Cho Jaebeom , Noh Myungkyung , Hyun Seung Yeob , Lee Ho-Young 
Published: July 2017

Abstract
Lung cancer is the leading cause of the cancer-related death worldwide. Despite extensive efforts for the cure of lung cancer, the effectiveness of currently available therapeutic regimens has been marginal and limited, and recurrence is still an inevitable consequence of anticancer therapies. Therefore, mechanistic understanding on the progression and relapse of lung cancer and finding out relevant targets are essential for development of efficacious therapeutic strategies. We have investigated mechanisms of chemoresistance by using subsets of lung cancer cell lines carrying acquired resistance to chemotherapies. These chemoresistant sublines of NSCLC cells exhibited a prominent downregulation of in vitro tumor activities, including proliferation, metabolism, and protein synthesis, but displayed increased tumor growth in vivo. Additional studies revealed that the chemoresistant sublines experienced increased secretion of various soluble factors that led to increases in proliferation and stemness of drug-naïve cancer cells and recruitment of macrophages, establishing tumor microenvironment (TME) prone to tumor recurrence. We further demonstrate a pivotal role of regulator of G protein signaling 2 (RGS2) in tumor-promoting cell-cell communications, ultimately leading to chemoresistance. RGS2 disrupted chemotherapy-induced apoptosis and secretion of soluble factors involved in cellular communications in TME by regulating unfolded protein responses, a typical cellular event associated with downregulation of protein synthesis. Mechanistically, RGS2 induced proteasome-mediated protein degradation of a component of eukaryotic translation initiation factor complexes through direct interaction, resulting in blockade of the CAP-dependent protein translation. RGS2 expression was elevated in tumors derived from patients with lung cancer compared with normal counterparts and significantly associated with poor clinical outcomes. These findings suggest that RGS2 is a novel biomarker responsible for chemoresistance by establishing tumor-promoting TME and can be a potential therapeutic target for the treatment of lung cancer with chemoresistance.
Citation Format: Hye-Young Min, Shin-Hyung Park, Ho Jin Lee, Jaebeom Cho, Myungkyung Noh, Seung Yeob Hyun, Ho-Young Lee. ER-stress induced translational regulation by RGS2 leads to tumor-promoting microenvironment and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3188. doi:10.1158/1538-7445.AM2017-3188