bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1211: Role of anchorage-independence in signaling pathway activation and cell survival in invasive breast cancer cell lines
Authors: Daubriac Julien , Boucher Yves 
Published: February 2011

Abstract
Resistance to anoikis - apoptosis induced by loss of matrix anchorage - is a key step in the metastatic process. In several cancer cell types including breast cancer cells, the anoikis-suppressing effect appears to be mediated by the PI3-kinase/Akt and MAP kinase signaling pathways. The aim of this study was to determine the involvement of signaling pathways in anoikis resistance in metastatic breast cancer cell lines. To study anoikis resistance, metastatic MDA-MB-231 and 4T1 cells were cultured on poly-HEMA-coated plates. Cell death was determined by detecting the sub-diploid population, by flow cytometry. Western analysis was used to assess the levels of phospho-Akt, phospho-p38 and cleaved-caspase-3. Our results show that loss of anchorage in MDA-231 cells reduces phospho-Akt levels, whereas in 4T1 cells - under both adherent and non-adherent conditions - the elevated level of phospho-Akt was not modified. Nevertheless, 4T1 cells undergo anoikis, which was dependent in part on the cleavage of caspase-3. In contrast, MDA-MB-231 cells were anoikis-resistant. Anoikis resistance correlated with the activation of p38 MAP-kinase. p38 phosphorylation was reduced in non-adherent 4T1 cells, whereas there was significantly higher levels of phosphorylated p38 in non-adherent than adherent MDA-MB-231 cells. The activation of p38 MAP kinase has been implicated in SDF1-CXCR4 signaling. One recent study has shown that CXCR4 inhibits anoikis in MDA-MB-231 cells, suggesting that CXCR4 or p38 blockade may induce anoikis in breast cancer. Thus our findings show that two metastatic breast cancer cell lines exhibit different sensitivity to anoikis, which is potentially associated with p38 MAP-kinase activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1211.
Abstract 1214: TIMP-1 and the TIMP-1 interacting cell surface protein CD63 in cultured astrocytoma derived spheroids: expression and co-expression with stem cell markers
Authors: Aaberg-Jessen Charlotte , Schrøder Henrik D. , Andersen Claus , Brünner Nils , Kristensen Bjarne W. 
Published: February 2011

Abstract
In previous studies we have shown that the immunohistochemical expression of TIMP-1 (tissue inhibitor of metalloproteinases-1) and CD63 increases with tumor grade in astrocytomas grade II-IV. Moreover, we demonstrated that a high TIMP-1 protein expression in glioblastomas was associated with a shorter overall patient survival. Recent studies have suggested that TIMP-1 can prevent chemo-induced apoptosis and in a study, using human breast epithelial cells (MCF10A), it was demonstrated that the interaction of TIMP-1 and CD63 is necessary for the TIMP-1 anti-apoptotic pathway. The aim of the present study was to investigate the expression of TIMP-1 and CD63 in cultured organotypic multicellular spheroids (OMS) and cell line spheroids (CLS) derived from astrocytomas in order to assess spheroid models for future studies involving TIMP-1, CD63 and chemo-resistance. By investigating the spheroids immunohistochemically, we wanted to elucidate if TIMP-1 and CD63 are co-expressed within the spheroids and whether they are expressed by tumor stem like-cells, since these cells are known to be more resistant to chemotherapeutic treatment. In the present study OMS from nine astrocytomas and CLS from three commercial astrocytoma cell lines were included as well as the glioblastoma tumor stem cell line SJ-1 made in our laboratory. In general high levels of CD63 protein was detected in all the original tumors, whereas TIMP-1 was moderately expressed. TIMP-1 and CD63 expression in OMS was similar to the expression in the original tumors. TIMP-1 was expressed at low to moderate levels in CLS, whereas CD63 was expressed by all tumor cells in all spheroids. TIMP-1/CD63 double immunofluorescence staining was performed on selected OMS and CLS showing tumor cells expressing both proteins. Furthermore, double staining was performed with TIMP-1 and the stem cell markers CD133, nestin and Sox2 demonstrating that a population of the tumor stem like-cells expressed TIMP-1. In conclusion, this study shows that spheroid models can be used in future studies investigating the role of TIMP-1 and CD63 in chemo-induced apoptosis. Furthermore, these results indicate that a fraction of the tumor stem like-cells could be protected by TIMP-1/CD63 interaction.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1214.
Abstract 1219: Tubulin binding to mitochondrial VDAC: A new regulator of oxidative metabolism and apoptosis? A new role for tubulin
Authors: Sackett Dan L. , Begaye Adrian 
Published: February 2011

Abstract
Tubulin binding to the outer mitochondrial membrane (OMM) was first reported many years ago but the function was unknown; we showed recently that dimeric tubulin binds to VDAC, the major metabolite channel in the OMM, and that this results in closing the channel to ATP-ADP exchange, with a consequent drop in oxidative phosphorylation. This could act as a regulator of normal oxidative metabolism, but excess tubulin binding could also lead to changes in the inner membrane potential, and possibly lead to mitochondrial swelling and triggering of apoptosis. To evaluate the plausibility of this mechanism for either regulation of normal metabolism or induction of apoptosis, the concentrations of tubulin and VDAC in the cell need to be known, as a huge discrepancy in either direction could make the mechanism unlikely. We have used semiquantitative Western blots to measure the concentrations of tubulin and VDAC in total cell extracts from a number of cancer cell lines. As expected, we found tubulin to be an abundant protein (∼0.5 % of total protein), but we also found VDAC to be more abundant than perhaps commonly thought (∼0.2 % of total protein). Thus we conclude that tubulin regulation of VDAC permeability is a plausible mechanism. Further experiments are underway to test this mechanism and its role in induction of apoptosis by chemotherapy agents, especially microtubule-directed ones.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1219.
Abstract 1221: Apoptosis is regulated by MCPH1 via p38 MAPK
Authors: Jo Yong Hwa , Choi Yongung Eun , Park Hyun Mi , Yoon Kyung-sik 
Published: February 2011

Abstract
Microcephalin (MCPH1) is a member of the BRCA1 COOH terminal (BRCT) domain family of protein that involved in the cellular response to DNA damage. MCPH1 gene are associated with primary microcephaly (OMIM 251200), premature chromosome condensation, homologous DNA repair, chromosomal integrity, cell cycle arrest, telomerase activity and apoptosis. Recently reports, And MCPH1 is regulated the p53 phosphorylation in apoptosis, and enhanced E2F1-dependent apoptosis and the role of MCPH1 in p73 induction during DNA damage. And E2F1 activation leads to a transient increase in phosphorylation of the MAPK p38 and also leads to phosphorylation of p53 in apoptosis. But it is not unclear mechanisms that MCPH1/ E2F1 binging induced phosphorylation of p38 MAPK. We have used western blotting and immunopresipitation for detecting protein expression and also real-time PCR for RNA expression. Cell lines were used MCF7, MDA-MB231, MCF10A and U2OS. We use the anti-cancer drugs, as cisplatin and doxorubicin for induced the apoptosis. Anti-cancer drugs are induced the MCPH1 protein expression for 2h∼6h, but reduced for 24h. We show the binging between E2F1and MCPH1and p38 MAPK expressions. And MCPH1 regulates p38 expression in apoptosis.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1221.
Abstract 1226: The AH receptor plays a key role in mediating IL6 production in head and neck tumor cell lines
Authors: DiNatale Brett , Perdew Gary H. 
Published: February 2011

Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor conventionally viewed as binding exogenous ligands and mediating gene transcription through DNA binding. Our research has uncovered various structurally distinct ligands, both exogenous and endogenous, that are capable of binding the AHR. We have also recently shown that combinatorial treatment of human breast and cervical cancer cell lines with an AHR ligand and an inflammatory signal results in synergistic induction of interleukin 6 (IL6). Squamous cell cancer of the head and neck is an umbrella term for malignancies developing in numerous locations, including the pharynx, larynx, tongue, and oral cavity. These tumors are often aggressive in nature, with high rates of metastasis to regional lymph nodes. Treatment has historically included radical or modified neck dissection to remove lymph nodes and frequent adjuvant chemotherapy and/or radiation therapy. IL6 production within HNSCC microenvironments both by cancer cells and by tumor-infiltrating macrophages has been shown to correlate with invasive, proliferative, and anti-apoptotic abilities of HNSCC cells, as well as human disease prognosis and recurrence rates. In studying a number of HNSCC cell lines, we have found many to have relatively high basal IL6 production. Using HNSCC2095 as an example, the AHR dependency of basal IL6 production was shown by means of siRNA-mediated AHR knockdown, as well as mediation of basal IL6 transcription following treatment with an AHR antagonist. ChIP assays reveal a significant level of basal AHR occupancy at the IL6 promoter, and antagonist treatment leads to dismissal of the AHR and a combination of coactivators. Similarly, AHR dismissal results in higher occupancy of transcriptional repressors. Key activators lost with AHR dismissal include p65, HDAC3, and BRG1. Following AHR dismissal, an increased presence of dimethylated histone H3 and HDAC1 occurs; both of which are typically repressive. Dismissal of the AHR from the IL6 promoter also leads to a decrease in the IL6-induced STAT3 signaling feedback loop seen in HNSCC lines. Constitutively active STAT3 has been examined as a therapeutic target in HNSCC due to its ability to increase tumor growth and anti-apoptotic effects. Our research shows that AHR binding to the IL6 promoter in HNSCC lines is required for constitutive cytokine production and plays a key role in STAT3 activation. These findings highlight the AHR as a potential target in mediating the autocrine loop of pro-growth signaling in human head and neck cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1226.
Abstract 123: Cooperative regulation between proliferative signals by activated Ras and inhibitors of apoptosis (IAPs) in gliomagenesis
Authors: Mukherjee Joydeep , Wolf Amparo , Hawkins Cynthia , Guha Abhijit 
Published: February 2011

Abstract
Transformation requires not only aberrant proliferation through signaling pathways such as activated Ras as demonstrated by our lab in GBMs, but also aberrant inhibition of regulators of apoptosis. Towards the latter, little is known about the expression and function of a family of proteins known as Inhibitors of Apoptosis Proteins (IAPs), which includes cIAP1, cIAP2, XIAP and Survivin, in GBMs. Human tumors which are prevalent in activating Ras mutations, such as colon and pancreatic cancers, produce high amounts of Survivin. We hypothesize that elevated activity of Ras in GBMs, as previously described by us, leads to aberrant expression of IAPs in GBMs and through its anti-apoptotic functions plays a role in glioma transformation.
Our previously described GFAP:12V-HaRas (RasB8) transgenic mouse glioma model was utilized. Elevated expression of activated Ras in the mouse gliomas was accompanied with increased expression of XIAP and Survivin. This was also prevalent in expression in human GBM cells, with elevated Ras activity. Knockdown of Ha-Ras in human and mouse GBM cells, by transfecting with couple of siRNA targeted against Ha-Ras gene, significantly decreased XIAP and Survivin levels. Knockdown of Ha-Ras in the mouse and human GBM cells increased their sensitivity to apoptosis inducing chemotherapy.
Current experiments include a genetic approach to down regulate Ras activity, by expression of a dominant-negative form of the Ha-Ras (Ha-Ras N17), in GBM cells and evaluating regulation of XIAP and Survivin expression. These experiments will be complemented with farnesyl transferase inhibitors to also inhibit Ras activity in the glioma cells. A Tet-inducible strategy to over express activated Ha-Ras in both transformed and non-transformed mouse and human astrocytes is being undertaken. These in vitro studies will be complemented by in vivo studies involving breeding our RasB8 glioma model to double transgenics with GFAP-Cre regulated decreased expression of Survivinflox/flox in astrocytes, with a postulated decrease in gliomagenic potential. The results to date and those underway are highly suggestive of the thesis that elevated Ras activity leads to glial transformation by not only mitogenic signals, but also by cooperative expression of anti-apoptotic proteins, such as IAPS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 123.
Abstract 1233: AP-1 transcription factor is involved in breast cancer cell proliferation mediated by progestins
Authors: Flaqué María C. Díaz , Beguelin Wendy , Rosemblit Cinthia , Proietti Cecilia , Rivas Martin A. , Tkach Mercedes , Charreau Eduardo H. , Schillaci Roxana , Elizalde Patricia 
Published: February 2011

Abstract
Accumulating evidence has shown the involvement of the progesterone receptor (PR) in breast cancer development. We and others have also shown that progestin are able to induce cyclin D1 expression, a key regulatory molecule that does not contain a progesterone response element (PRE) in the promoter region. In the present study, we propose a novel mechanism in which progestin controls breast cancer growth through the integration of rapid PR signaling and a transcriptional mechanism (tethering), that involves progesterone-bound PR interaction with AP-1 transcription factor (composed of Jun and Fos family members), at specific AP-1 binding sites (TRE) in the cyclin D1 promoter. MPA treatment of breast cancer cells induced an increase in the levels of cyclin D1 protein. We have also shown that MPA treatment of breast cancer cells induced an increase in the levels of c-jun and c-fos phosphorylation. To study the effect of MPA on AP-1-mediated transcriptional activity, cells were transiently transfected with a luciferase reporter plasmid containing three copies of TRE. We found that MPA enhanced AP-1 transcriptional activity and this effect was abolished by the antiprogestin RU486. We assessed the specific association of AP-1 and PR to the TRE region of the cyclin D1 gene in the context of living cells, by performing Chromatin Immunoprecipitation Assays. We found that MPA treatment induced c-jun, c-fos and PR recruitment to the cyclin D1 promoter. These data identify, for the first time, the interaction between AP-1 and PR regulating cyclin D1 transcription by tethering to DNA-bound at TRE site. Furthermore, we found that the inhibition of c-fos and c-jun activation by the use of dominant negative forms of these proteins (A-Fos and TAM-67 respectively) completely blocked progestin-induced cyclin D1 expression and in vitro breast cancer cell growth. Finally, we addressed the effect of targeting AP-1 in in vivo MPA-dependent growth of C4HD progestin-dependent murine mammary tumor. Transfection of C4HD cells with TAM-67 or A-Fos DN expression vectors significantly inhibited these cells’ ability to form tumors in syngeneic mice. Histological examination determined a striking decrease in histological grade in both groups in comparison to control group.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1233.
Abstract 1237: WT1, Wnt signaling and E-cadherin in prostate cancer
Authors: Brett Adina , Eisermann Kurtis , Fraizer Gail 
Published: February 2011

Abstract
Prostate carcinoma is the most common malignancy and second leading cause of death among American men. The molecular mechanisms that control the progression of this type of cancer are still poorly understood. Among the genes proposed to play a role in prostate cancer is the zinc finger transcription factor, WT1. Previous studies in our lab have shown WT1 protein in a majority of high grade prostate tumor sections with little or no WT1 staining in non-neoplastic or benign prostatic hyperplasia (BPH) tissues. However, a mechanistic role for WT1 in prostate cancer has not been established. Recently, WT1 has been associated with the Wnt signaling pathway and Beta catenin, the central molecule in the pathway. The cytoplasmic levels of Beta catenin can be regulated through the canonical Wnt signaling or through the intracellular adhesion complex where it binds to E-cadherin. Importantly, E-cadherin has previously been identified as a WT1 target gene in NIH 3T3 cells. The objective of this study was to determine whether WT1 might regulate genes that, in turn, regulate the levels of Beta catenin in prostate cancer cells. First potential WT1 binding sites were identified in the promoters of two candidate genes, GSK3 Beta and E-cadherin, using a bioinformatics approach. Then the effect of transfection of LNCaP prostate cancer cells with GFP-tagged WT1 expression constructs was tested by quantitative real time PCR (QRT-PCR). In vivo evidence of direct binding of these gene promoters by WT1 protein was obtained by Chromatin immunoprecipitation (ChIP) of GFP/WT1 transfected LNCaP cells. Using evolutionary conservation analysis we identified two WT1 binding sites in the E-cadherin promoter conserved among primate species and one that was conserved among primates, rodents and dog. QRT- PCR results showed a decrease in E-cadherin transcripts in GFP/WT1 transfected LNCaP cells, compared with untransfected cells. ChIP was used to demonstrate that this effect on E-cadherin expression was direct and mediated by DNA binding to the E-cadherin promoter in vivo. Overall these results suggest that WT1 modulates E-cadherin and the Wnt signaling pathway in LNCaP cells. These findings suggest a novel mechanism for proliferation and migration of prostate cancer cells and ultimately may contribute towards an improved cancer therapy.
This work was supported by NIHR15CA11360 (GF) and GSS KSU grant(AB)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1237.
Abstract 1238: Diagnostic and therapeutic potential of nuclear receptor expression in lung cancer
Authors: Jeong Yangsik , Lee Woochang , Xie Yang , Bookout Angie L. , Kim Bong-hyun , Girard Luc , Minna John D. , Mangelsdorf David J. 
Published: February 2011

Abstract
Lung cancer is the leading cause of cancer related death with the highest mortality among cancers. Although several studies have been published on prognostic biomarkers for lung cancer patients, little attention has been given to identify diagnostic biomarkers and new therapeutic targets. Nuclear receptors are druggable targets due to their ligand-controlled activity, and indeed have become well-established therapeutic tools for treating patients with strong estrogen receptor alpha (ERα)-positive breast cancer or androgen-dependent prostate cancer. Our aims in this study were (1) to investigate if the NR superfamily as a whole or individually showed diagnostic potential, (2) to evaluate NRs as therapeutic targets using both in vitro cell lines and in vivo xenografts.
Utilizing quantitative real-time PCR (QPCR), we profiled the mRNA expression of the NR superfamily in a panel of 56 lung cell lines, including 5 normal human bronchial epithelial cells, 10 immortalized cell lines, 14 small cell lung cancers (SCLCs), and 27 non-SCLCs. All individual cell lines were characterized by DNA fingerprinting and gene expression using the affymetrix U133 A plus B microarray. Unsupervised cluster analysis of the QPCR profile and the microarray signature of the NR superfamily revealed that the NR superfamily was able to segregate normal/immortalized cells from tumor cell lines, and SCLCs from non-SCLCs. Further analysis identified subsets of NRs responsible for this discriminatory ability. In addition, using publicly available microarray datasets, we found that the NR signature has a predictive power with an accuracy of 79% for lung cancer incidence in smokers (n=129), in which a prediction model was constructed in a training set (n=77) using penalized logistic regression (PLR), and validated in a testing cohort (n=52). Finally, preclinical evaluation of a panel of NRs ¬- androgen receptor, ERα, vitamin D receptor, and peroxisome proliferators-activated receptor gamma - for their therapeutic potential showed receptor-specific and ligand-dependent cell growth responses in lung cancer cell lines. Evaluation of one receptor/ligand pair using a mouse xenograft model confirmed receptor-specific tumor growth response in vivo.
Collectively, our study provides preclinical evidence that the expression of the NR superfamily yields theragnostic (therapy plus diagnosis) information for predicting lung cancer type and incidence, while simultaneously offering therapeutic targets for potential lung cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1238.