bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1306: Synergistic function of a novel cell cycle regulator, Ecdysoneless with oncogenic Ras in the regulation of cell cycle and transformation
Authors: Bele Aditya , Mirza Sameer , Mir Riyaz , Mohibi Shakur , Band Hamid , Band Vimla 
Published: May 2015

Abstract
We have previously identified the mammalian ortholog of Drosophila ecdysoneless (Ecd) protein as a novel and essential regulator of Rb-E2F-dependent cell cycle progression. Consistent with role of Ecd in cell cycle, our recent studies show Ecd is overexpressed in breast cancer cell lines as well as in ductal carcinoma in situ and infiltrating ductal carcinomas of the breast. To explore the mechanism of Ecd overexpression and its correlation with oncogenesis, we overexpressed either Ecd alone, HRas-61L alone or both genes together in hTERT-immortalized human mammary epithelial cells (hMECs). These transfectants were then examined for their oncogenic properties. We observed while vector infected cells do not exhibit anchorage independence, all three transfectants showed increase in anchorage independent proliferation, particularly Ecd+Ras showed a significant increase in anchorage independence in comparison with either Ecd or Ras. Similarly, other oncogenic traits such as proliferation on matrigel, invasion and migration were dramatically increased when both genes were expressed in comparison with individual genes. Further analysis showed Ecd+Ras-expressing hMECs were unable to synchronize completely after growth factor deprivation and showed rapid progression into cell cycle, demonstrating synergy in altered cell cycle pathways in these cells. Most significantly, Ecd+Ras expressing hMECs were able to form tumors when implanted into mammary fat pads of NOD-SCID mice, whereas no tumors were observed with Ecd or Ras alone. These results demonstrate complete transformation of hMECs by overexpression of Ecd together with mutant Ras.
Considering the known oncogenic role of Ras in human cancer and the known role of Ecd in cell cycle, these data are highly significant and present a novel synergistic pathway for mammary cell transformation. Current studies are directed towards defining the mechanism of synergy between Ecd and Ras in cellular transformation.
Citation Format: Aditya Bele, Sameer Mirza, Riyaz Mir, Shakur Mohibi, Hamid Band, Vimla Band. Synergistic function of a novel cell cycle regulator, Ecdysoneless with oncogenic Ras in the regulation of cell cycle and transformation. [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 1306. doi:10.1158/1538-7445.AM2014-1306
Abstract 1308: Functional inhibition of HSP90 induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer
Authors: Nagaraju Ganji Purnachandra , Willingham Field F. , Woods Kevin E. , Sullivan Patrick , Landry Jerome C. , Diaz Roberto , El-Rayes Bassel F. 
Published: May 2015

Abstract
Purpose Objectives: Cell cycle progression and DNA synthesis are essential steps in cancer cell growth and resistance. Thymidylate synthase (TS) is a therapeutic target for 5FU. Ganetespib is a potent functional inhibitor of HSP90 currently under evaluation in clinical trials. We tested the hypothesis that HSP90 functional inhibition by ganetespib can inhibit cell cycle progression and downregulate TS levels in colorectal cell lines.
Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50 nM for 24 hours. Western blot and Real time-PCR analyses were carried out to determine the effect of ganetespib on different signal molecules involved in cell cycle arrest and DNA synthesis. A subcutaneous xenograft mouse model was used to evaluate the in vivo effects of ganetespib. Pre and post ganetespib treatment tumor biopsies from patients with rectal cancer on a phase I trial of ganetespib were analyzed using RT-PCR.
Results: Treatment with ganetespib inhibited cyclin D1, pRb and E2F-1 at the transcriptional and translational level and induced p21, leading to G0/G1 cell cycle arrest. HSP90 knockdown inhibited E2F-1 and TS protein and mRNA levels in both cell lines. Arrest in the G0/G1 phase was associated with downregulation of the transcription factor E2F-1 and its target gene TS. Similar effects were observed in tumors from animals treated with ganetespib. Further, ganetespib treatment significantly inhibited the tumor growth. Inhibition of cyclin D1, Rb, E2F-1, TS and upregulation of p21 at transcriptional levels were observed in post treatment rectal tumor biopsies obtained from patients receiving ganetespib.
Conclusion: In this study, we present preclinical and clinical data to support the use of HSP90 inhibitors in colorectal cancer based on their ability to reduce expression of proteins important for DNA repair and cell cycle progression leading to cell cycle arrest and tumor shrinkage. Accordingly, combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in colorectal cancer.
Citation Format: Ganji Purnachandra Nagaraju, Field F. Willingham, Kevin E. Woods, Patrick Sullivan, Jerome C. Landry, Roberto Diaz, Bassel F. El-Rayes. Functional inhibition of HSP90 induces G0/G1 arrest and downregulates thymidylate synthase in colorectal 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 1308. doi:10.1158/1538-7445.AM2014-1308
Abstract 1309: Identification of aurora kinase a as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
Authors: Yeh Chun-Nan , Yen Chueh-Chuan , Chen Yeng-Yang , Cheng Chi-Tung , Huang Shih-Chiang , Chang Ting-Wei , Yao Fang-Yi , Lin Yung-Chan , Wen Yao-Shan , Chiang Kun-Chun , Chen Jen-Shi , Yeh Ta-Sen , Tzeng Cheng-Hwai , Chao Ta-Chung , Fletcher Jonathan A. 
Published: May 2015

Abstract
Purpose: Although imatinib mesylate (IM) has revolutionized the management of gastrointestinal stromal tumors (GISTs), drug resistance remains a challenge. Previous studies have shown that the expression of aurora kinase A (AURKA) predicts recurrence in patients with primary surgically-resected GISTs. The current study aims to evaluate the significance of AURKA as an unfavorable prognostic marker for advanced GISTs, and provides evidence that AURKA could be a potential treatment target of GISTs.
Experimental Design: The prognostic significance of AURKA, along with other clinicopathological factors, was analyzed in a cohort of 99 IM-treated patients with advanced GISTs using immunohistochemistry. The potential use of an AURKA inhibitor as therapeutic agent against GISTs was also tested in GIST cell lines.
Results: Among 99 enrolled patients, poor performance status, large tumor size, drug response, and AURKA overexpression were independent poor prognostic factors for progression-free survival (PFS). For overall survival (OS), only large tumor size and AURKA overexpression were identified as independent unfavorable factors. In an in vitro study, MLN8237, an AURKA inhibitor, was demonstrated to inhibit growth of both IM-sensitive and IM-resistant GIST cells in a concentration-dependent manner. The inhibitory effect of MLN8237 on GIST cells could be attributed to the induction of G2/M arrest, apoptosis, and senescence, possibly through up-regulation of pro-apoptotic proteins.
Conclusions: Our study showed that AURAK is an independent poor prognostic factor for both PFS and OS in patients with advanced GISTs treated with IM. AURKA inhibitor could be used as therapeutic agent for both IM-sensitive and IM-resistant GISTs.
Citation Format: Chun-Nan Yeh, Chueh-Chuan Yen, Yeng-Yang Chen, Chi-Tung Cheng, Shih-Chiang Huang, Ting-Wei Chang, Fang-Yi Yao, Yung-Chan Lin, Yao-Shan Wen, Kun-Chun Chiang, Jen-Shi Chen, Ta-Sen Yeh, Cheng-Hwai Tzeng, Ta-Chung Chao, Jonathan A. Fletcher. Identification of aurora kinase a as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors. [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 1309. doi:10.1158/1538-7445.AM2014-1309
Abstract 131: C-kit induces epithelial-mesenchymal transition and contributes to salivary adenoid cystic cancer progression
Authors: Liang Xinhua , Tang Ya-ling , Jiang Jian , Fan Yun-long 
Published: May 2015

Abstract
Epithelial-mesenchymal transition (EMT) is associated with salivary adenoid cystic cancer (ACC) progression and metastasis. Here, we report that ectopic overexpression of c-kit in ACC cell lines is sufficient for acquisition of mesenchymal traits, enhanced cell invasion, along with stem cell properties defined by the presence of a CD133+/CD44+ cell subpopulation. c-kit positively regulated expression of known EMT inducers, also activating TGF-βto contribute to EMT. c-kit itself was induced by TGF-βin ACC cell lines and required for TGF-β-induced EMT. Xenograft experiments showed that c-kit cooperated with oncogenic Ras to promote tumorigenesis in vivo. Finally, in human specimens of ACC, we found that c-kit was abnormally overexpressed and correlated with the prognosis of ACC. Our findings define an important function for c-kit in ACC progression by orchestrating EMT, and they implicate this gene product as a marker of poor prognosis in this disease.
Citation Format: Xinhua Liang, Ya-ling Tang, Jian Jiang, Yun-long Fan. C-kit induces epithelial-mesenchymal transition and contributes to salivary adenoid cystic cancer progression. [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 131. doi:10.1158/1538-7445.AM2014-131
Abstract 1322: Novel CDK4/6 inhibitors provide robust antitumor activity in a murine model of luminal breast cancer
Authors: Roberts Patrick J. , Darr David B. , Bisi John E. , Strum Jay C. 
Published: May 2015

Abstract
Introduction: Selective CDK4/6 inhibitors have emerged as attractive antineoplastic agents due to the importance of CDK4/6 activity in regulating cell proliferation. We have identified a series of orally available, potent and selective dual CDK4/6 inhibitors (G1T100182, G1T100183, G1T101551). Preclinical characterization of these compounds indicates that they inhibit CDK4 and CDK6 with an IC50 of 0.7-1.0 nM and 5-6 nM, respectively. In Rb competent tumor cells, these compounds potently inhibit Rb phosphorylation resulting in a G1 arrest. Here we assess the in vivo efficacy of these compounds in a genetically engineered mouse model of luminal breast cancer.
Methods: MMTV-Neu mice were housed and therapeutic response assessed in the UNC Lineberger Comprehensive Cancer Center's Mouse Phase I Unit (MP1U). Compounds were supplied by G1 Therapeutics, Inc. Tumors were serially assessed weekly using caliper measurements. Therapeutic intervention began once tumors reached 40-64mm3 and continued for 28 consecutive days. Tumor volume was calculated using the formula ((Width2) x Length)/2). All compounds were administered orally via medicated diets. RECIST criteria were used to assess objective response rates.
Results: Significant objective responses were noted in mice treated with G1T100182, G1T100183, G1T101551. Treatments produced modest reversible myelosuppression, but where otherwise well tolerated with no other clinical signs of toxicity or deaths associated with toxicity. A linear regression t-test was used to determine statistical significance of tumor volume changes over time. All treatment cohorts demonstrated statistically significant improvement when compared to un-treated mice; G1T100182, p&lt;0.0001; G1T100183, p=0.0001; G1T101551, p&lt;0.0001.
Conclusions: In summary, we have identified a series of orally active, potent, and selective small molecule inhibitors of CDK4/6 that may provide therapeutic benefit to cancer patients with tumors that have functional Rb protein.
Complete ResponsePartial ResponseStable DiseaseProgressive DiseaseORR % (CR+PR+SD/PD)Mean % Change in Tumor VolNo Treatment00090 (0/9)500G1T1001821510100 (7/0)-70G1T100183141185 (6/1)-67G1T1015511250100 (8/0)-40
Citation Format: Patrick J. Roberts, David B. Darr, John E. Bisi, Jay C. Strum. Novel CDK4/6 inhibitors provide robust antitumor activity in a murine model of luminal 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 1322. doi:10.1158/1538-7445.AM2014-1322
Abstract 1337: BH3-mimetic gossypol promotes autophagy to inhibit the proliferation of mutant BRAF melanoma cells with high expression of p21Cip1
Authors: Lee Michael , Jang Gun-Hee , Ahn Jun-Ho , Kim Na-Yeon 
Published: May 2015

Abstract
Gossypol is a BH3-mimetic small-molecule pan-inhibitor of Bcl-2. In this study, we described the potential therapeutic effects of gossypol on BRAF inhibitor-resistant melanoma cells. We found that gossypol retained its efficacy in mutant melanoma clones resistant to BRAF inhibitor through a mechanism independent of MEK-ERK inhibition. Gossypol caused G2/M arrest in BRAF mutant A375P cells with high expression of p21Cip1, regardless of their drug resistance. Interestingly, we determined that the lack of gossypol-induced mitotic arrest in BRAF-WT-harboring SK-MEL-2 cells was associated with a low level of p21Cip1 expression. In addition, gossypol preferentially induced autophagy and apoptosis in the gossypol-sensitive cells and not in the gossypol-resistant SK-MEL-2 cells, which suggests that apoptosis and autophagy can occur simultaneously and act as cooperative partners for the induction of cell death. Taken together, these results suggest that gossypol may exhibit potential for the treatment of BRAF inhibitor-resistant tumors, but a functional p21Cip1 is a prerequisite for a positive response to its clinical application.
Citation Format: Michael Lee, Gun-Hee Jang, Jun-Ho Ahn, Na-Yeon Kim. BH3-mimetic gossypol promotes autophagy to inhibit the proliferation of mutant BRAF melanoma cells with high expression of p21Cip1. [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 1337. doi:10.1158/1538-7445.AM2014-1337
Abstract 134: HNF4α inhibits liver cancer metastasis via suppression of NF-кB activity
Authors: Ning Bei-Fang , Liu Jiao , Xu Wen-Ping , Yin Chuan , Zhang Xin , Xie Wei-Fen 
Published: May 2015

Abstract
BACKGROUND & AIMS: Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) metastasis remains largely unknown.
METHODS: 429 HCC tissues were involved in the correlation analysis of HNF4α levels with tumor features and patient outcomes. Effect of HNF4α on HCC metastasis was monitored through in vivo imaging system. Expression of HNF4α, RelA(p65) or microRNAs in human HCCs was determined by Real-time PCR, western blot or immunohistochemistry. Point mutation and ChIP assay were performed to detect the interaction of HNF4α with the promoter of target microRNA. 3’UTR reporter assay was conducted to determine the regulation of RelA by microRNAs.
RESULTS: Reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. HNF4α suppressed HCC metastasis through inhibiting RelA expression and NFκB activity. miR-7 and miR-124, which were transcriptionally up-regulated by HNF4α, repressed RelA expression via interaction with RelA-3’UTR. Herein, HNF4α suppresses NF-κB activity and RelA expression via a miR-7 and miR-124-dependent manner. Moreover, combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis.
CONCLUSIONS: Considering the importance of HNF4α and NF-κB in chronic liver disease, the suppression of NF-κB by HNF4α is not only essential in connecting hepatic inflammation and tumorigenesis, but also indicates novel strategy in HCC prevention and therapy.
Citation Format: Bei-Fang Ning, Jiao Liu, Wen-Ping Xu, Chuan Yin, Xin Zhang, Wei-Fen Xie. HNF4α inhibits liver cancer metastasis via suppression of NF-кB activity. [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 134. doi:10.1158/1538-7445.AM2014-134
Abstract 1341: Rapid decrease of ATP followed by necrosis-like cell death in bladder cancer cells after exposure to high-dose chemotherapeutics used in intravesical therapy
Authors: Yoshida Takahiro , Okuyama Hiroaki , Nakayama Masashi , Nishimura Kazuo , Nonomura Norio , Inoue Masahiro 
Published: May 2015

Abstract
Objectives) Non-muscle invasive bladder cancer is often treated by intravesical chemotherapy following transurethral resection. Mechanism of the effect of intravesical chemotherapy remains elusive. In this experiment, we studied cell death mechanism induced by high-dose chemotherapeutics using a novel culture method for primary cancer cells.
Materials and methods) We have developed a new culture method which enables preparation and culture of primary cancer cells as multicellular spheroids which are termed cancer tissue-originated spheroids (CTOSs) (Okuyama 2013 J Urol). First we generated a bladder cancer patient-derived xenograft. We prepared CTOS from the xenograft, and exposed to high-dose (1mg/ml) or low-dose (0.01mg/ml) of epirubicin (e-ADM) or mitomycin C (MMC) for 2 hours. We investigated absorption of chemotherapeutics into CTOSs and assessed the mode of cell death. Next, we prepared CTOSs directly from surgical specimens of bladder cancer and tested the individual responses after exposure to high-dose e-ADM and MMC.
Results) At high dose, e-ADM was promptly and homogenously delivered into cancer cells in the CTOSs. High-dose e-ADM and MMC decreased ATP levels in CTOSs within an hour accompanied with mitochondrial swelling and reduction of mitochondrial membrane potential, while plasma membrane integrity was mainteined. Some of the molecules in mitochondrial apoptotic pathway were subsequently activated, while at later time point the cells lost integrity of cell membrane without DNA laddering. In contrast, CTOSs exposed to low-dose of e-ADM or MMC exhibited typical DNA laddering. Intriguingly, the decrease of ATP levels by e-ADM and MMC was varied among CTOSs derived from 20 surgical specimens.
Conclusions) High-dose chemotherapeutics used in intravesical therapy may induce necrosis-like cell death, different from typical apoptosis caused by chemotherapeutics at the dose of systemic chemotherapy. Each bladder cancer may have a different response to high-dose chemotherapeutics used in intravesical therapy, indicating necessity of chemosensitivity test aiming for personalized medicine.
Citation Format: Takahiro Yoshida, Hiroaki Okuyama, Masashi Nakayama, Kazuo Nishimura, Norio Nonomura, Masahiro Inoue. Rapid decrease of ATP followed by necrosis-like cell death in bladder cancer cells after exposure to high-dose chemotherapeutics used in intravesical therapy. [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 1341. doi:10.1158/1538-7445.AM2014-1341
Abstract 1347: The role of cell-cell contacts in the survival of extracellular matrix detached mammary epithelial cells
Authors: Rayavarapu Raju , Pagani Nicholas , Heiden Brendan , Schafer Zachary T. 
Published: May 2015

Abstract
Normal epithelial cells require attachment to the extracellular matrix (ECM) in order to survive. When detached from the ECM, normal cells will undergo apoptosis through a process known as anoikis. The ErbB2 receptor tyrosine kinase is well known to antagonize anoikis although the precise molecular mechanisms are not entirely known. Interestingly, we have discovered that the overexpression of ErbB2 in non-malignant mammary epithelial cells (MCF-10A) results in substantial aggregation of cells that coincides with protection from anoikis. Therefore, we were interested in understanding if these aggregates could be involved in the evasion of anoikis induction. We found that the disruption of cell-cell contacts in ErbB2-overexpressing MCF-10A cells (using methylcellulose or by antagonizing the formation of adherens junctions) induces caspase activation. Furthermore, in cells that form large aggregates, ErbB2 can physically interact with E-cadherin and EGFR in a fashion that prevents the internalization of EGFR and ultimately its lysosome mediated degradation. The disruption of aggregation causes the ErbB2/EGFR/E-Cadherin complex to fall apart and subsequently results in EGFR degradation in the lysosome. This degradation of EGFR diminishes signaling through the MAPK pathway which prevents the induction of anoikis. In summary, these data suggest that oncogenic signaling through ErbB2 promotes the formation of cellular aggregates that function to prevent EGFR from degradation and subsequently to block the induction of anoikis.
Citation Format: Raju Rayavarapu, Nicholas Pagani, Brendan Heiden, Zachary T. Schafer. The role of cell-cell contacts in the survival of extracellular matrix detached mammary 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 1347. doi:10.1158/1538-7445.AM2014-1347