bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2713: Small-molecule FASN inhibitors promote growth inhibition growth and apoptosis of breast cancer
Authors: Lupu Ruth , Guerrico Anatilde Gonzalez , Khurana Ashwani , Heuer Timothy , Kemble George , KVP Chandra Mohan 
Published: May 2015

Abstract
Increased de novo lipogenesis due to enhanced expression of several lipogenic enzymes has been found in many types of human cancers. Fatty acid synthase (FASN), the key enzyme in the de novo lipogenesis pathway, is one of the most commonly over-expressed lipogenic enzymes. Studies in the past decade have recognized FASN overexpression as a molecular marker for poor prognosis and malignant phenotype of many cancers. Tumor-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, has also been suggested to play an active part in the development, maintenance, and metastatic progression of human cancers. More recently, FASN has been implicated in contributing to cellular resistance to several anticancer treatments. A variety of agents have been developed to target lipogenic enzymes and the key regulators involved in lipid metabolism in cancer cell for therapeutic purposes. The development of several FASN inhibitors has been reported from both academic labs and industries. When used in in vitro, xenograft and genetically induced mouse model studies, these inhibitors have supported FASN as an excellent target. A new generation of FASN inhibitors was developed at 3-V Biosciences that are highly specific, reversible inhibitors of FASN. One compound in this series, TVB-2640, is orally bioavailable and has progressed into Phase 1 clinical studies. The effect of two anti-FASN drugs in this series, TVB-3150 and TVB-3199 were tested for their effect on breast cancer cells. We demonstrated that the EC50 is between 9-50 nM, depending on the drug and the tested cell line. We then demonstrated that the drugs inhibited the anchorage-dependent and -independent growth of FASN expressing cells in a dose dependent manner. The apparent mechanism by which the FASN inhibitors promote inhibition of growth is by inducing apoptotic cell death in a time- and dose-dependent manner that involves regulation of apoptotic and pro-apoptotic proteins. Furthermore, the combination of the anti-FASN drugs with small molecule inhibitors of the antiapoptotic proteins Bcl-2 and Bcl-xL significantly increased the apoptotic effect in a synergistic manner compared to either of the synthetic inhibitors alone. In vivo studies demonstrate tumor growth inhibition without toxicity. Clinical development of a first-in-class, orally active, potent, and reversible FASN inhibitor as a novel cancer therapeutic is ongoing.
Citation Format: Ruth Lupu, Anatilde Gonzalez Guerrico, Ashwani Khurana, Timothy Heuer, George Kemble, Chandra Mohan KVP. Small-molecule FASN inhibitors promote growth inhibition growth and apoptosis of breast cancer. [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 2713. doi:10.1158/1538-7445.AM2014-2713
Abstract 2719: Use of abiraterone against a luminal androgen receptor breast cancer cell line
Authors: Rao Krishna A. , Modur Vishnu , Ghosh Sumana 
Published: May 2015

Abstract
Background: Data from this pre-clinical model suggests that the LAR TNBC subtype is unique and may respond to novel hormonal agents such as bicalutamide or abiraterone. The LAR subtype represents 11 % of all TNBC (which represent 20% of all breast cancers). Thus, positive studies of abiraterone could potentially extend the application of abiraterone to an additional 2% of all breast cancer patients, who could be treated in the metastatic, neoadjuvant, and adjuvant setting (for five years) with hormonal maintenance therapy. We, therefore, conducted studies of abiraterone on LAR TNBC cell line, MDA-MB-453. .
Methods: i). Cell proliferation- Cell proliferation will be done by plating 500,000 cells in triplicate Petri dishes and measuring cell number over a six day period between parent cells and cellstreated with the following varying concentrations of abiraterone: 100 ng/ml, 250 ng/ml, and 400 ng/ml. ii).Cell cycle effects- Cells were incubated for 24 hours with abiraterone and then lifted from the plate with trypsin/EDTA (0.5%/0.1%) and fixed overnight in 80% ethanol. This was followed by staining in PBS with 10 ug/ml of propidium iodide for twenty minutes at room temperature. Flow cytometry was performed in our facility, and data was obtained on the percentage of the cell population in various points of the cell cycle. iii). Apoptosis and necrosis assay (Annexin-V-PI assay)- Cells were harvested at 72 hours post-seeding and incubation with abiraterone and washed with ice-cold PBS, followed by staining with 1ug/ml of PI and 5ul of Alexa Fluor® 488 annexin V in 100ul of annexin binding buffer (10 mM Hepes/NaOH, pH 7.4, 140 mM NaCl, 2.5 mM CaCl2). After the incubation at room temperature for 15 minutes, 400ul of ice-cold annexin binding buffer was added and stained cells were analyzed by Becton-Dickinson FACSCalibur Flow Cytometer.
Results: Abiraterone caused a significant impact on cell proliferation and promoted apoptosis in the MDA-MB-453 population. Cell cycle effects were also noted with abiraterone treatment.
Conclusion: Abiraterone has activity against MDA-MB-453, a breast cancer cell line known to express luminal androgen receptor. The results suggest that further studies may be warranted with this agent against this unique subtype of breast cancer.
Citation Format: Krishna A. Rao, Vishnu Modur, Sumana Ghosh. Use of abiraterone against a luminal androgen receptor breast cancer cell line. [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 2719. doi:10.1158/1538-7445.AM2014-2719
Abstract 2731: PELP1 promotes DNA double-strand break repair via alternative-NHEJ: Implications in therapy resistance
Authors: Krishnan Samaya R. , Nair Binoj C. , Sareddy Gangadhara R. , Mann Monica , Vadlamudi Ratna K. 
Published: May 2015

Abstract
Estrogen Receptor positive breast cancer is commonly treated with hormonal therapy; however, many patients acquire therapy resistance, a major clinical problem. Recent evidence suggests that the accumulation of chromosomal abnormalities via increased error-prone Alternative-Non-Homologous End Joining (A-NHEJ) DNA repair pathway could contribute to breast cancer therapy resistance. Proline, Glutamic acid, Leucine rich Protein-1 (PELP1), an oncogenic co-regulator for transcription factors, is commonly overexpressed in breast cancer, and its deregulation has been implicated in therapy resistance. Our recent studies identified PELP1 as a novel substrate of the DNA damage response (DDR) kinases. In this study, we discovered that PELP1 regulates the A-NHEJ pathway, and we developed a novel peptide drug that targets PELP1-A-NHEJ axis for the treatment of therapy resistance. Our results suggest that PELP1 is phosphorylated at Ser1033 by DDR kinases and phosphorylated PELP1 co-localizes with the gamma-H2AX foci. Using Homologous Recombination (HR) and NHEJ pathway specific reporter assays, we found that PELP1 knockdown decreases NHEJ, with no apparent effect on the HR pathway. Further, using A-NHEJ specific reporter cell line, we found that PELP1 knockdown decreased the frequency of A-NHEJ, while PELP1 overexpression increased the repair frequency. PELP1's ability to regulate A-NHEJ pathway was further confirmed by sequencing repaired plasmids and by quantitating the degree of end resection. More importantly, metaphase chromosome spreads revealed gross chromosomal abnormalities in PELP1 deregulated breast cancer cells. Mechanistic studies revealed that PELP1 interacts with Mre11, and modulates the degree of end resection at the DNA double strand breaks. Mapping studies identified the C-terminus of PELP1 as the binding site for Mre11. Using yeast based genetic screen composed of 10 million peptides, we identified a unique peptide, PIP3 that binds the C-terminus of PELP1. We developed a stapled peptide of PIP3 (sPIP3), which functioned as a potent cytotoxic agent for breast cancer cells with little activity on normal cells. Further, sPIP3 efficiently inhibited the A-NHEJ pathway and significantly, reduced survival and promoted apoptosis of therapy resistant model cells. Collectively, these findings suggest that PELP1 plays a critical role in the A-NHEJ pathway and sPIP3 represents a novel drug for the treatment of therapy resistant breast cancer.
Citation Format: Samaya R. Krishnan, Binoj C. Nair, Gangadhara R. Sareddy, Monica Mann, Ratna K. Vadlamudi. PELP1 promotes DNA double-strand break repair via alternative-NHEJ: Implications in therapy resistance. [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 2731. doi:10.1158/1538-7445.AM2014-2731
Abstract 275: Clinical and demographic comparison between bladder cancer and upper urinary tract urothelial carcinoma in Taiwan
Authors: Tung Min-Che , Chen Hsin-An , Su Chih-Ming , Huang Ming-Te , Chiou Hung-Yi , Wang Yuan-Hung 
Published: May 2015

Abstract
Objective Urothelial carcinoma (UC) which is derived from the urothelium of the urinary tract includes cancers of bladder, renal pelvis and ureter. The aim of this study was to compare clinical and demographic features between bladder and upper urinary tract urothelial carcinoma in Taiwan.
Material and methods The present study recruited a total of 736 histopathological confirmed UC cases, which consisted of 470 bladder cancer and 266 upper urinary tract UC (UTUC) cases. Clinical and demographic characteristics were collected by structured question interview and medical chart review. This study was approved by the institutional review boards of the collaborated hospitals. The effects of risk factors on UC risk were estimated by odds ratios (ORs) and its 95% confidence intervals (CIs) using unconditional logistic regression. All statistical analyses were performed using Statistical Analysis Software for Windows, version 9.1 (SAS Institute, Cary, NC).
Results The frequencies of cigarette smoking and alcohol consumption in bladder cancer cases were significantly higher than that in UTUC cases. Compared with bladder cancer cases, UTUC cases also had a significantly higher frequencies of advanced tumor stage (T2-4) and poorly differentiation (G3). In a multivariate- adjusted logistic regression, we found the advanced stage (T2-4) was a significant prognostic factor of overall survival for bladder cancer and UTUC cases, especially the risk of the T4 stage in UTUC cases.
Conclusion Our results showed that some clinical and demographic features between bladder and UTUC cases were different in Taiwan.
Keywords: bladder cancer; ueothelial carcinoma; upper urinary tract
Citation Format: Min-Che Tung, Hsin-An Chen, Chih-Ming Su, Ming-Te Huang, Hung-Yi Chiou, Yuan-Hung Wang. Clinical and demographic comparison between bladder cancer and upper urinary tract urothelial carcinoma in Taiwan. [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 275. doi:10.1158/1538-7445.AM2014-275
Abstract 2754: Induction of Sp1 factor by CYP1B1 inhibits TRAIL-mediated apoptotic pathway
Authors: Kwon Yeo-Jung , Park Nahee , Shin Sangyun , Ye Dong-Jin , Hong Mihye , Chun Young-Jin 
Published: May 2015

Abstract
Human cytochrome P450 1B1 (CYP1B1) belongs to the CYP1 family and is known as a major enzyme for estradiol 4-hydroxylation. It has been reported that CYP1B1 expression is higher in the tumor tissues than the normal ones, especially in hormone-related cancers such as breast, ovarian and prostate. Previously, we identified that CYP1B1 induces cell proliferation by activation of Wnt/β-catenin signal pathway. To explore the role of CYP1B1 on cancer cell proliferation further, we investigated whether CYP1B1 blocks apoptotic pathways. Using Western blot and RT-PCR, the expression of TRAIL was examined in MCF-7 cells, and we found that CYP1B1 overexpression or treatment with a CYP1B1 inducer, 7, 12-dimethylbenz[α]anthracene (DMBA) caused suppression of TRAIL and its receptors (DR4 and DR5) expression. However, when cells were treated with CYP1B1 siRNA or a selective CYP1B1 inhibitor, tetramethoxystilbene (TMS), expression of TRAIL and its receptors were significantly increased. Sp1, a zinc finger-containing transcription factor, has been reported to suppress TRAIL gene expression by binding TRAIL promoter. Interestingly, CYP1B1 overexpression and DMBA induced Sp1 expression and TMS was able to prevent DMBA-induced Sp1 expression. Sp1 knockdown with siRNA suppressed c-FLIP, an inhibitor protein of TRAIL-mediated apoptosis while it enhanced TRAIL and DR4 expression. These results were reversed by Sp1 overexpession. Moreover, attenuation of Sp1 DNA binding activity using mithramycin A, a Sp1 binding inhibitor, resulted in recovery of TRAIL expression suppressed by DMBA. Taken together, these data suggest that CYP1B1 prevents apoptosis via TRAIL suppression and this is mediated by Sp1 induction.
Citation Format: Yeo-Jung Kwon, Nahee Park, Sangyun Shin, Dong-Jin Ye, Mihye Hong, Young-Jin Chun. Induction of Sp1 factor by CYP1B1 inhibits TRAIL-mediated apoptotic 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 2754. doi:10.1158/1538-7445.AM2014-2754
Abstract 276: Appalachian mountaintop mining particulate matter induces malignant transformation and tumorigenesis of human lung epithelial cells
Authors: Luanpitpong Sudjit , Luo Juhua , Kneuckles Travis , Hendryx Michael , Rojanasakul Yon 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer death, and after smoking, environmental and occupational exposure is the major cause. West Virginia (WV), the biggest coal mining state in Appalachia, ranks the third highest rate of lung cancer incidence in the United States. Our epidemiological studies suggest that living near WV mountaintop coal mining (MTM) activities is a contributing factor of the high lung cancer risk. The purpose of this study was to investigate the effect of MTM particle exposure on cell transformation and tumorigenesis of human lung epithelial cells. Air particulate matter (PM) collected within one mile of active MTM site in Edwight, WV (PMMTM), consisting of silica (Si, 48%) and molybdenum (Mo, 29%) as major constituents, was used for cell exposure studies. As control, PM collected from the neighboring areas that do not have coal mining in Green Bank, WV (PMCON) was used. Chronic exposure (3 months) of non-tumorigenic human lung epithelial BEAS-2B cells to sub-cytotoxic concentration (1 μg/mL) of PMMTM, but not PMCON, was found to induce malignant transformation of the cells, as indicated by loss of contact inhibition and anchorage-independent cell growth. The PMMTM-transformed cells also induced tumor formation in vivo using a xenograft mouse model. Exposure to Mo (1 μg/mL), but not Si, similarly induced malignant transformation and tumorigenesis of the lung epithelial cells, suggesting that Mo may be a key contributing factor of PMMTM pathologic effects.
Citation Format: Sudjit Luanpitpong, Juhua Luo, Travis Kneuckles, Michael Hendryx, Yon Rojanasakul. Appalachian mountaintop mining particulate matter induces malignant transformation and tumorigenesis of human lung epithelial 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 276. doi:10.1158/1538-7445.AM2014-276
Abstract 2762: Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations
Authors: Yamada Tadaaki , Carbone David Paul , Takeuchi Shinji , Fujita Naoya , Yano Seiji 
Published: May 2015

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show favorable effects in EGFR mutant lung cancer. However, responders eventually develop acquired resistance almost without exception, and secondary T790M mutations in EGFR account for approximately 50% of the acquired resistance. Recent studies indicated that EGFR mutant lung cancer cells are dependent on EGFR/Akt signaling for survival even after acquired T790M secondary mutation. Akt kinase-interacting protein1 (Aki1) is a scaffold protein that binds to wild-type EGFR after EGF ligand stimulation, maintains signaling specificity, and mediates activating signal to the PI3K/PDK1/Akt pathway. We hypothesized that Aki1 may play important roles in signal transduction in EGFR mutant lung cancer cells. Here, we showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M secondary mutation. Silencing of Aki1 inhibited phosphorylation of Akt and S6, and induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA markedly inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 inhibited H1975 cell growth in combination with new generation EGFR-TKIs in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a key mediator of survival signaling from mutant EGFR, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M secondary mutation.
Citation Format: Tadaaki Yamada, David Paul Carbone, Shinji Takeuchi, Naoya Fujita, Seiji Yano. Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations. [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 2762. doi:10.1158/1538-7445.AM2014-2762
Abstract 2782: The effect of ERRFI1 as a novel AKT regulator on cell proliferation and response to therapy is cell context dependent
Authors: Hou Junmei , Bhinge Kaustubh N. , Wang Liewei 
Published: May 2015

Abstract
ERRFI1, a negative regulator of the EGFR family, is known to inhibit EGFR activation along with downstream of EGFR signaling. It is recognized as a tumor suppressor. However, ERRFI1 has multiple functions, and here, we present a novel function of ERRFI1. We found that it can directly interact with AKT and positively regulate AKT activity through regulation of AKT473 site by inhibiting PHLPP, the phosphatase access to AKT. The effect of this regulation on cell proliferation and on response to chemotherapy is cell context dependent, e.g. EGFR levels. We hypothesize that in cancer cells with high EGFR expression, down regulation of ERRFI1 enhances EGFR signaling, while on the other hand, increases AKT dephosphorylation. The strength of these two opposing signals will determine the eventual cellular phenotypes. In cancer cells with low EGFR expression, the direct effect of ERRFI1 on AKT is dominant, resulting in activation of AKT. To test these hypotheses, we knockdown ERRFI1 in multiple human cancer cell lines with different EGFR levels. Knockdown of ERRFI1 in high EGFR expressing cells resulted in an increase of cell proliferation and resistance to gemcitabine treatment, and this effect was due to the dominant negative effect of ERRFI1on EGFR, which was confirmed by increased EGFR signaling. Knockdown of ERRFI1 in cell lines with moderate level of EGFR also increased cell proliferation and resistance to gemcitabine, although biochemically, down regulation of ERRFI1 reduced AKT pS473 levels, but increased ERK/MAPK signaling. The addition of EGFR inhibitor, gefitinib, overcame gemcitabine resistance due to downregualtion of ERRFI1. In contrary, in cell lines with low level of EGFR, ERRFI1 positively regulated AKT signaling via directly binding to AKT and blocking PHLPP access to AKT. Therefore, down-regulation of ERRFI1 inhibited cell proliferation and sensitized cells to gemcitabine. In summary, we identified a novel function of ERRFI1 as a positive AKT regulator and its effect on cell proliferation and response to therapy is cell context dependent, e.g. EGFR levels. These results provide us insights into the dual roles of ERRFI1 in regulation of EGFR and AKT pathway and would help us to better individualize cancer therapy.
Citation Format: Junmei Hou, Kaustubh N. Bhinge, Liewei Wang. The effect of ERRFI1 as a novel AKT regulator on cell proliferation and response to therapy is cell context dependent. [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 2782. doi:10.1158/1538-7445.AM2014-2782
Abstract 2785: LYN is a new prognostic and therapeutic target in non-small cell lung cancer
Authors: Kim Yu Jin , Sung Minjung , Park Min Jeong , Shin Young Kee , Choi Yoon-La 
Published: May 2015

Abstract
SRC family kinases (SFKs) have a strong rationale as a clinical strategy in non-small cell lung cancer (NSCLC). Unfortunately, the reviewed study showed disappointing activity of SFK inhibitor dasatinib in molecularly unselected patient cohort. Therefore, the studies in NSCLC should be investigated to identify patients more likely to benefit from dasatinib either as monotherapy or in combination with other agents. Here, we considered that LYN may play specific roles in lung cancer and therefore analysed survival prognosis according to the expression of LYN and the effect of dasatinib on the inhibition of cell growth and LYN activity. We evaluated LYN expression by immunohistochemistry on 446 NSCLCs using paraffin-embedded tissues. Elevated LYN expression level of NSCLCs, especially in adenocarcinoma, female, and non-smoker, affected poor overall survival (OS, P=0.036). In lung adenocarcinoma cell lines, LYN expression impacted on cell proliferation, migration and invasion. Dasatinib treatment resulted in decreased cell viability in most of these cell lines. Also, we found that dasatinib suppressed active tyrosine phosphorylation of LYN. In the resistant cell lines, H23 and SK-LU-1, which showed elevated epidermal growth factor (EGFR) and MET activities, combined treatment of EGFR or MET inhibitor with dasatinib revealed the synergistic effects on decreased cell viability. Our findings highly suggest that LYN has potential as a new selected target molecule of SFKs in the treatment of NSCLCs.
Citation Format: Yu Jin Kim, Minjung Sung, Min Jeong Park, Young Kee Shin, Yoon-La Choi. LYN is a new prognostic and therapeutic target in non-small cell lung cancer. [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 2785. doi:10.1158/1538-7445.AM2014-2785