bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 210: Id4 inhibition of twist1-mediated autocrine PDGF signaling inhibits growth and promotes apoptosis of glioblastoma-derived stem cell cultures
Authors: Rahme Gilbert J. , Israel Mark A. 
Published: May 2015

Abstract
Glioblastoma Multiforme (GBM) is the most common, aggressive, and lethal primary brain tumor. A hallmark of GBM is the resistance of tumor stem cells to chemotherapy resulting in tumor recurrence and progression decreasing the quality of life and causing patient death. The prevention of GBM recurrence after chemotherapy by eliminating cancer stem cells enhances survival in genetically engineered mouse models; however, the signal transduction networks that control cancer stem cell survival and proliferation remain poorly understood.
We have discovered that decreased expression of Id4, a dominant negative helix-loop-helix transcription factor, is associated with the proliferation and survival of sphere cultures from GBM-derived cell lines, which are enriched for cancer stem cells. In striking contrast, Id4 expression did not affect proliferation or apoptosis in differentiated, adherent cultures of these same cell lines. Moreover, the cell lines we examined required autocrine PDGF signaling for growth. We found that Id4 inhibited autocrine PDGF signaling in cancer stem cell enriched cultures by suppressing the expression of platelet-derived growth factor receptor α (PDGFRα). In these studies we found that Id4 mediated inhibition of PDGFRα expression was mediated through the antagonistic interaction between Id4 and Twist1, a basic helix-loop-helix transcription factor. This observation is consistent with our previously reported finding that Id4, uniquely among the Id family of proteins, binds to and antagonizes Twist1. Further, using the Rembrandt and TCGA databases, we found that Id4 expression levels directly correlate with glioma patient survival and can predict the level of PDGFRα expression. These data provide strong evidence that Id4 may regulate GBM stem cell survival and thereby contribute to GBM tumor progression. Along with our recent report demonstrating that Id4 can block invasion of GBM by silencing Twist1-mediated MMP2 expression, these findings suggest that pharmacological targeting of the Id4/Twist1 complex might provide opportunities to reduce the lethality of GBM by regulating both GBM invasion and tumor stem cell maintenance.
Citation Format: Gilbert J. Rahme, Mark A. Israel. Id4 inhibition of twist1-mediated autocrine PDGF signaling inhibits growth and promotes apoptosis of glioblastoma-derived stem cell cultures. [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 210. doi:10.1158/1538-7445.AM2014-210
Abstract 2101: Role of CDK8 in estrogen receptor signaling in breast cancers
Authors: McDermott Martina , Gyorffy Balazs , Lim Chang-uk , Chumanevich Alexander , Yang Zhengguan , Chen Mengqian , Catroppo James F. , Roninson Igor , Broude Eugenia V. 
Published: May 2015

Abstract
The majority of breast cancers (BrCa) overexpress estrogen receptor (ER)α, which regulates transcription and drives estrogen-stimulated proliferation of ER+ tumor cells. ER+ patients usually receive adjuvant anti-estrogen therapy based on ER modification, downregulation, or estrogen depletion. Tumors frequently develop resistance to anti-estrogen therapy through various mechanisms, which may involve stimulation of ER itself or of downstream mediators of ER-driven transcription, as well as activation of alternative proliferation pathways, in particular those driven by HER2/EGFR. The treatment efficacy of hormone-resistant BrCa could be greatly augmented by targeting new druggable mediators of ER activity. We have now identified a transcription-regulating oncogenic kinase CDK8 as a potentiator of ER signaling and ER-driven BrCa cell proliferation. Immunohistochemical staining of breast tissue arrays and bioinformatics analysis of gene expression microarray data of breast cancer patients revealed that CDK8 is overexpressed in BrCa and that higher CDK8 expression correlates with the failure of systemic therapy. Among systemically untreated patients, higher CDK8 expression was correlated with shorter relapse-free survival in a subset of ER+ tumors that expressed the lowest levels of ERα. This correlation suggested that CDK8 could play a role in the progression of ER+ breast cancers with reduced levels of ER, possibly by stimulating the mitogenic effects of ER-mediated transcription. Indeed, a selective small-molecule CDK8 inhibitor (Senexin A) decreased estrogen-induced ER-dependent transcription and inhibited estrogen-stimulated proliferation of ER+ BrCa cell lines. Microarray analysis revealed that CDK8 inhibition diminished the induction of genes that show rapid and sustained activation by estrogen in ER+ cells. CDK8 inhibition had an additive effect in combination with anti-estrogens in ER+ BrCa and a synergistic effect with fulvestrant in BrCa cells resistant to estrogen deprivation. Some of these cell lines also express HER2/EGFR, and CDK8 inhibition in combination with a HER2/EGFR inhibitor lapatinib synergistically inhibited the growth of these cells. These results suggest that combining anti-estrogen and anti-CDK8 therapy may be more effective than conventional hormone therapy for ER+ BrCa.
Citation Format: Martina McDermott, Balazs Gyorffy, Chang-uk Lim, Alexander Chumanevich, Zhengguan Yang, Mengqian Chen, James F. Catroppo, Igor Roninson, Eugenia V. Broude. Role of CDK8 in estrogen receptor signaling in breast cancers. [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 2101. doi:10.1158/1538-7445.AM2014-2101
Abstract 2106: Estrogen receptor alpha drives proliferation of prostate cancer through PI3K and MAPK signaling
Authors: Takizawa Itsuhiro , Lawrence Mitchell , Pearson Helen , Pedersen John , Pouliot Normand ,   Australian Prostate Cancer BioResource, Humbert Patrick , Furic Luc , Risbridger Gail 
Published: May 2015

Abstract
Prostate cancer, a hormone-dependent disease of aging men, occurs as the relative levels of estrogen compared to testosterone are increasing. Indeed, high doses of estrogen, in combination with androgens, can initiate prostate cancer. This effect is attributed to the activity of the estrogen receptor α (ERα), but a paucity of suitable models means that the precise role of ERα in prostate cancer is still poorly understood.
In this study we observed increased ERα expression in three different models of prostate cancer, PTEN null mice, Hi-Myc mice, and high grade human tumor specimens. Within the PTEN null prostate, there was a consistent pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This pattern significantly correlated with the levels of the proliferative marker Ki67. There was also a significant correlation between ERα and Ki67 within individual malignant glands in the anterior prostate. Furthermore, we demonstrated that ERα sustained the in vitro proliferation of cells derived from a PTEN null tumor in 2D and 3D assays. There was a significant decrease in proliferation in cells treated with TPSF, a non-competitive ERα antagonist, or with ERα-specific shRNA. Loss of ERα caused a significant decrease in the levels of MYC and other ERα target genes. It also reduced the activity of both the PI3K and MAPK pathways as measured by decreased levels of phosphorylated erk1/2, S6 kinase and other downstream factors. This effect was reversed in rescue experiments with expression constructs for both full length ERα, capable of genomic and non-genomic actions, and membrane-only ERα, only able to trigger rapid non-genomic signalling.
Collectively, these results demonstrate that ERα levels increase in prostate cancer, which promotes proliferation through classical genomic and rapid non-genomic signalling.
Citation Format: Itsuhiro Takizawa, Mitchell Lawrence, Helen Pearson, John Pedersen, Normand Pouliot, Australian Prostate Cancer BioResource, Patrick Humbert, Luc Furic, Gail Risbridger. Estrogen receptor alpha drives proliferation of prostate cancer through PI3K and MAPK signaling. [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 2106. doi:10.1158/1538-7445.AM2014-2106
Abstract 2108: Estrogen non genomic signalling is activated in tamoxifen-resistant breast cancer
Authors: Poulard Coralie , Rambaud Juliette , Cohen Pascale , Migliaccio Antimo , Corbo Laura , Marangoni Elisabetta , Romancer Muriel L. 
Published: May 2015

Abstract
Introduction: Although the presence of nuclear estrogen receptor (ERα) is widely used to guide breast cancer therapy, less attention has been paid to the receptor cytoplasmic signalling. We have already shown that arginine methylation of ERα is essential for E2-non genomic pathway triggered by ERα interaction with PI3K and c-Src thereby propagating the signal to downstream transduction cascades (Le Romancer et al, Mol Cell, 2008). Recently, we have found that this pathway is operative in vivo and is activated in aggressive tumors representing a new potential target for breast cancer therapy (Poulard et al, Embo Mol Med, 2012). In addition, the cross talk between ERα and growth factor signalling has emerged as a critical factor in endocrine resistance. The aim of this study was to investigate the receptor cytoplasmic signalling in human ERα-positive breast cancer with acquired resistance to tamoxifen.
Experimental procedures: The activation of cytoplasmic ER signalling pathway was investigated in tamoxifen resistant MCF-7 cells and in patient-derived xenografts (PDX) of ERα-positive breast cancer with acquired resistance in vivo to tamoxifen. In addition, tamoxifen-resistant PDX models were treated with tamoxifen, fulvestrant and everolimus, during 90 days. ERα interactions with Src and PI3K were investigated by Proximity Ligation Assay (PLA) in formalin-fixed tumors, a technology which enables to investigate protein/protein interactions in tissues.
Results: Interestingly, we detected an increase of ERα/Src/PI3K expression in tamoxifen resistant versus parental MCF-7 cells. This result was confirmed in one PDX model where we found a significant increase of ERα/Src/PI3K expression in the tamoxifen-resistant tumor compared to the corresponding parental xenograft. Finally, the analysis of treated tumors revealed a significant decrease of ERα/Src/PI3K expression in the fulvestrant-treated tumors as well as in tumors treated by the everolimus and fulvestrant combination.
In conclusion these results show that ERα cytoplasmic signalling is associated to acquisition of tamoxifen resistance both in cell line and patients-derived xenografts. In addition, ERα cytoplasmic signalling appears to be affected in tumors responding to alternative treatments such as fulvestrant or everolimus. Targeted therapies against ERα, Src and PI3K are in progress and could constitute a new approach to circumvent resistance to endocrine therapies.
Citation Format: Coralie Poulard, Juliette Rambaud, Pascale Cohen, Antimo Migliaccio, Laura Corbo, Elisabetta Marangoni, Muriel Le Romancer. Estrogen non genomic signalling is activated in tamoxifen-resistant 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 2108. doi:10.1158/1538-7445.AM2014-2108
Abstract 2110: Molecular characterization of everolimus-resistant cell lines established from estrogen depletion-resistant MCF-7
Authors: Kimura Mariko , Hanamura Toru , Niwa Toshifumi , Yamaguchi Yuri , Endo Itaru , Hayashi Shin-ichi 
Published: May 2015

Abstract
mTOR inhibitor everolimus has been considered as a promising agent for breast cancer treatment especially among estrogen receptor (ER) positive postmenopausal advanced breast cancer. As expected, combination therapy of everolimus and steroidal aromatase inhibitor (AI) showed remarkable clinical efficacy for the first line nonsteroidal AI treatment failure patients in BOLERO-2 trial. However, the subsequent treatment after refractory to that therapy remains a great matter. We already reported several types of long term estrogen-depletion resistant (EDR) cell lines from MCF-7-E10, which has been constitutively ERE-GFP-transfected to monitor ER activity in living cells (Fujiki N et al., J Steroid Biochem Mol Biol. 2013 Oct 13;139C:61-72). They mimic AI resistance and these EDR cells have been characterized as the followings. 1) Type 1 as ER positive (ERE-GFP positive), constitutive ER overexpression without estrogen, and PI3K/Akt/mTOR pathway upregulated. 2) Type 2 as ER negative conversion (ERE-GFP negative) and IGF-1R/JNK signaling pathway upregulated. Then with those two types of sub-cell lines, we generated everolimus resistant cells after long term exposure to everolimus in estrogen depleted medium. Those everolimus resistant (EVR) cells are equivalent to resistance to the combination therapy of AI and everolimus as the second line endocrine treatment after the first line AI treatment failure. Though everolimus extremely inhibited cell proliferation of two EDR cell lines, everolimus resistant cells named as Type 1-EVR, Type 2-EVR no longer responded to everolimus. ER expression and estrogen sensitivity of two types of EVR cells were similar to those of the parental cells, respectively. Pure anti-estrogen fulvestrant inhibited cell proliferation of Type1-EVR cells. On the other hand, Type2-EVR did not respond to fulvestrant but JNK inhibitor inhibited the cell growth. Phosphorylation status of p70S6K and 4E-BP1 were different among individual parental EDR cells and EVR cells. Type1-EVR showed much higher expression of phosphorylation of MAP-kinase than the parental cells. In contrast, Type2-EVR expressed phosphorylation of MAP-kinase less than the parental cells. As above, the mechanism of acquired resistance to everolimus was likely to be different between those two sub-cell lines. This finding implies that different mechanisms of AI resistance follow different types of everolimus resistance.
Citation Format: Mariko Kimura, Toru Hanamura, Toshifumi Niwa, Yuri Yamaguchi, Itaru Endo, Shin-ichi Hayashi. Molecular characterization of everolimus-resistant cell lines established from estrogen depletion-resistant MCF-7. [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 2110. doi:10.1158/1538-7445.AM2014-2110
Abstract 2111: Role of gene repression by estrogen in invasiveness of breast cancer cells
Authors: Patki Mugdha , Salazar Marcela d'Alincourt , Trumbly Robert , Ratnam Manohar 
Published: May 2015

Abstract
More than 75% of breast tumors are estrogen receptor (ER)-positive and require estrogen for their growth and survival. Long-term adjuvant therapies that disrupt estrogen signaling, in particular tamoxifen and aromatase inhibitors, are a mainstay in breast cancer treatment. The principal focus of mechanistic studies evaluating the role of estrogen in breast cancer proliferation has been on gene activation by estrogen and its antagonism by anti-estrogens. Gene repression by estrogen and its antagonism by anti-estrogens have unclear physiological and therapeutic consequence in breast cancer. In this study, we found that estrogen-repressed genes but not estrogen-activated genes overlapped the gene overexpression signature of clinical progression of ductal carcinoma in situ to invasive ductal carcinoma. An extensive gene ontology analysis revealed that genes repressed by estrogen are enriched for functions known to collectively support breast cancer progression. In ER-positive breast cancer cells tamoxifen prevented gene repression by estrogen. In these cells, estrogen inhibited invasiveness in a manner that was opposed by tamoxifen. These effects of estrogen and tamoxifen on gene repression and invasiveness also occurred in Her2+/ER+ cells whose growth was hormone-independent and insensitive to tamoxifen. The effects were also independent of ErbB2 gene regulation by estrogen. Several ER co-repressors supported repression of the tumor progression genes by estrogen. Gene repression by estrogen was causally linked to inhibition of invasiveness as a co-repressor binding site mutation in ER that selectively disrupted the ability of estrogen to repress genes also prevented inhibition of invasiveness. Gene repression by estrogen involved ER binding at non-classical chromatin sites that was prevented by tamoxifen. The findings offer a mechanistic understanding of the invasive potential of ER+ breast cancer cells that have evaded growth inhibition during conventional anti-estrogen treatments.
Citation Format: Mugdha Patki, Marcela d'Alincourt Salazar, Robert Trumbly, Manohar Ratnam. Role of gene repression by estrogen in invasiveness of breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2111. doi:10.1158/1538-7445.AM2014-2111
Abstract 2113: Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy
Authors: Qi Yanfeng , Cao Bo , Zhang Guanyi , Xu Duo , Guo Zhiyong , Xiong Zhenggang , Plymate Stephen , Sartor Oliver , Zhang Haitao , Dong Yan 
Published: May 2015

Abstract
Androgen deprivation therapy, which disrupts androgen receptor (AR) signaling through androgen ablation or AR antagonists, is the first-line treatment for disseminated prostate cancer. While this regimen is effective initially, progression to the presently incurable and lethal stage, termed castration-resistant prostate cancer, invariably occurs. Upregulation of constitutively-active AR splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and ARv567es, two major AR-Vs, both facilitated AR-FL nuclear translocation in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but when dimerized with AR-FL, co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, AR-V levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a “rheostat” to control the response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.
Citation Format: Yanfeng Qi, Bo Cao, Guanyi Zhang, Duo Xu, Zhiyong Guo, Zhenggang Xiong, Stephen Plymate, Oliver Sartor, Haitao Zhang, Yan Dong. Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed 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 2113. doi:10.1158/1538-7445.AM2014-2113
Abstract 2117: Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells
Authors: COTTARD Félicie , ASMANE Irène , ERDMANN Eva , BERGERAT Jean-Pierre , KURTZ Jean-Emmanuel , CERALINE Jocelyn 
Published: May 2015

Abstract
Androgen receptor (AR) signaling pathway remains the main target of novel therapeutics for castration-resistant prostate cancer (CRPC). However, constitutively active AR variants lacking the carboxy-terminal region in CRPC lead to therapy inefficacy. Moreover, recent studies suggest that AR variants are expressed in primary prostate tumors and may contribute to tumor progression. The aim of this study was to investigate the impact of AR variants on tumor progression.
N-cadherin expression was analyzed in LNCaP cells overexpressing the wild type AR or a constitutively active AR variant by qRT-PCR, Western blot and immunofluorescence. We showed here for the first time that N-cadherin expression was increased in the presence of constitutively active AR variants. Moreover, this increased expression of N-cadherin in LNCaP overexpressing AR variants was negatively regulated by androgens.
Although N-cadherin expression is often associated with a downregulation of E-cadherin, this phenomenon was not observed in our model. Nevertheless, in addition to the increased expression of N-cadherin, an upregulation of other mesenchymal markers expression such as Vimentin, SNAIL and ZEB1 was observed in the presence of constitutively active AR variants.
In conclusion, our findings highlight novel consequences of constitutively active AR variants on the regulation of mesenchymal markers in prostate cancer.
Citation Format: Félicie COTTARD, Irène ASMANE, Eva ERDMANN, Jean-Pierre BERGERAT, Jean-Emmanuel KURTZ, Jocelyn CERALINE. Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2117. doi:10.1158/1538-7445.AM2014-2117