bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4229: The anti-estrogen effect of metformin in ERα+ breast cancer and tamoxifen resistant cell lines
Authors: Kim Jinkyoung , Lee Jiyun , Jang Soonyoung , Kim Chungyeul , Kim Aeree 
Published: May 2015

Abstract
Anti-estrogen therapy is still the most important systemic treatment to manage estrogen responsive breast cancer. Tamoxifen resistance is a major obstacle in treatment of ER-positive breast cancer. Recently, metformin, which is a biguanide derivative which is commonly used in the treatment of type II diabetes, has been emerged as a potential anti-cancer agent. We investigated if metformin had anti-estrogen effect in ER-positive breast cancer cell lines which are MCF-7, MDA-MB-361 as well as tamoxifen resistant cells (TR-MCF-7). Metformin inhibited the cell proliferation and the expression of ERα in dose-dependent manner in MCF-7 and TR-MCF-7 cells. Under stimulation of 17β-estradiol (E2), metformin inhibited the cell proliferation and expression of mRNA and protein of ERα in MCF-7 and TR-MCF-7 cells, while tamoxifen didn't affect E2 induced cell proliferation and ERα expression. This result indicates that metformin, as anti-estrogen agent, is superior to tamoxifen for targeting ER in breast cancer. We also identified that metformin inhibited E2 induced cell proliferation and expression of mRNA and protein of ERα in MDA-MB 361 cell line (ER+/Her-2+). We also analyzed estrogen responsive element (ERE) activity using by luciferase assay and identified metformin suppressed E2-inducible luciferase activity and expression of direct ER-regulated genes, such as c-myc, Cyclin D1 and pS2 and FOXA1, which were not inhibited by tamoxifen. In conclusion, metformin has a direct anti proliferative effect and anti-estrogen effect in MCF-7, TR-MCF-7 as well as MDA-MB-361 cell lines. These results suggest that metformin can be used as anti- estrogen in ER positive breast cancer (luminal A & B) and tamoxifen resistant breast cancer.
Citation Format: Jinkyoung Kim, Jiyun Lee, Soonyoung Jang, Chungyeul Kim, Aeree Kim. The anti-estrogen effect of metformin in ERα+ breast cancer and tamoxifen resistant cell lines. [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 4229. doi:10.1158/1538-7445.AM2014-4229
Abstract 681: Heat shock-mediated suppression of ODC protein expression in colorectal cancer cells
Authors: Wales Christina T.K. , Jacobs Aaron T. 
Published: May 2015

Abstract
Polyamines are small, positively charged metabolites that have important roles in several cancer hallmarks, including cell proliferation, invasion, and angiogenesis. Difluoromethylornithine (DFMO) is an FDA-approved drug that is in clinical trials for treatment of colorectal cancer. DFMO functions by inhibiting ornithine decarboxylase (ODC), which catalyzes the rate-limiting step in polyamine biosynthesis. By reducing polyamine levels, DFMO has shown much promise as an anti-cancer chemotherapeutic. One potential limitation to DFMO is that it causes a profound increase in ODC expression, which we suspect may counteract the intended use of the drug. However, strategies to suppress ODC expression would theoretically increase DFMO efficacy.
We have discovered that transient hyperthermia (heat shock, 42°C) causes a profound and rapid suppression in ODC protein levels in RKO colorectal cancer cells. To investigate the responsible mechanism, we began by examining ODC mRNA expression and stability. Hyperthermia caused only a moderate reduction in ODC transcript levels. Also, mRNA stability, which was assessed using actinomycin D, was not reduced by heat shock. We next examined the effect of hyperthermia on the control of ODC protein turnover, which is known to be mediated by ODC antizyme (OAZ1). We performed real-time PCR to assess the effect of heat shock on OAZ1 expression. Data reveal a significant increase in the level of OAZ1 transcript. Since heat shock is known to activate the transcription factor HSF1, we next investigated the role of HSF1 in OAZ1 induction. Using siRNA to silence HSF1, we found that the induction of OAZ1 by heat shock is fully dependent on HSF1 expression. In addition to heat shock, HSF1 is also activated by various chemotherapeutics, but most notably by Hsp90 inhibitors. We therefore tested if Hsp90 inhibitors, geldanamycin and 17-AAG could be used to induce OAZ1 and promote ODC turnover. These results show that both Hsp90 inhibitors caused a significant activation of HSF1, an induction in OAZ1 expression, and decrease in ODC protein levels. We therefore propose that Hsp90 inhibitors may be effective in attenuating ODC expression and polyamine metabolism. We suggest that they may be used in combination with DFMO to prevent the compensatory increase in ODC levels and increase anti-cancer effects.
Citation Format: Christina T.K. Wales, Aaron T. Jacobs. Heat shock-mediated suppression of ODC protein expression in colorectal 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 681. doi:10.1158/1538-7445.AM2014-681
Abstract 832: Pre-clinical development of EC1456: A potent Folate targeted Tubulysin SMDC
Authors: Reddy Joseph A. , Bloomfield Alicia , Nelson Melissa , Dorton Ryan , Vetzel Marilynn , Leamon Christopher P. 
Published: May 2015

Abstract
Folate targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide now being evaluated in a phase 3 trial in FR-positive ovarian cancer patients. We have now developed a new group of folate conjugated Tubulysins, of which EC1456 has emerged as a lead candidate for clinical development. Treatment of nude mice bearing folate receptor (FR) positive human xenografts with EC1456 led to complete remissions (CR's) or cures in 100% of the mice at various doses and schedules. The observed activity was not accompanied by any noticeable weight loss or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0 % CR's) was observed in EC1456-treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating EC1456's target-specific activity. The enhanced therapeutic index due to folate conjugation was also evidenced by the fact that the un-targeted free drug (tubulysin B or its hydrazide form) was found to be completely inactive even when administered at highly toxic dose levels. Furthermore, when challenged with larger tumors, EC1456 again displayed remarkable anti-tumor activity with 100% cures in tumors up to 750 mm3. Complete cures were also observed in other FR positive models such as MDA-MB-231 TNBC and M109 lung tumor models. In support of our clinical strategy to treat drug resistant FR-positive cancer patients we have also shown that EC1456 was highly active against FR expressing paclitaxel and cisplatin-resistant cell lines. Taken together, these studies demonstrated that EC1456 has significant anti-tumor growth activity and tolerability, thus lending support to the ongoing Phase 1 clinical evaluation of EC1456 for advanced malignancies.
Citation Format: Joseph A. Reddy, Alicia Bloomfield, Melissa Nelson, Ryan Dorton, Marilynn Vetzel, Christopher P. Leamon. Pre-clinical development of EC1456: A potent Folate targeted Tubulysin SMDC. [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 832. doi:10.1158/1538-7445.AM2014-832
Abstract P6-05-01: Endoplasmic reticulum resident protein transmembrane protein 33 (TMEM33) induces apoptosis via UPR signaling and autophagy in breast cancer cells
Authors: Hu Rong , Zhang Xiyuan , Hilakivi-Clarke Leena , Kasid Usha , Clarke Robert 
Published: May 2015

Abstract
Breast cancer is the most common cancer type in women, with expected incidence of around 232,670 new cases in the US alone each year. Endoplasmic reticulum stress (EnR stress) and the related unfolded protein response (UPR) are activated in breast cancer cells to promote cell survival and endocrine resistance. TMEM33 is a novel transmembrane protein that resides in the endoplasmic reticulum (EnR) and has been shown to activate two of the UPR branches (PERK; IRE1α). However, the cellular functions and underlying mechanism of this EnR resident protein remains largely unknown. In this study, we show that overexpression of TMEM33 induces robust cell death in breast cancer cells. TMEM33 overexpression strongly activates the pro-death JNK-p53 pathway, possibly through the activation of IRE1α. We also observe a significant inhibition of the downstream survivin (also called BIRC5), which is known to inhibit cell death by binding to caspases and blocking their activation. We further show that either the blockage of JNK activation with a small molecule inhibitor, or the overexpression of survivin, protects cells against TMEM33-induced apoptosis. In addition, we demonstrate that TMEM33 overexpression induces autophagy in breast cancer cells (changes in LC3 and p62 expression). Inhibition of autophagy with either the autophagy inhibitor chloroquine, or by knockdown of the autophagy gene Atg5, further sensitizes breast cancer cells to TMEM33 overexpression. Conversely, cell death induced by TMEM33 is decreased by overexpression of the autophagy gene Beclin 1. The findings in this study demonstrate that the novel EnR resident protein TMEM33 induces cell death by activating the IRE1α-JNK-p53-survivin pathway in breast cancer cells. Paradoxically, autophagy is also activated by TMEM33 but the prosurvival action is generally not sufficient to block all of the cell death signaling.
Citation Format: Rong Hu, Xiyuan Zhang, Leena Hilakivi-Clarke, Usha Kasid, Robert Clarke. Endoplasmic reticulum resident protein transmembrane protein 33 (TMEM33) induces apoptosis via UPR signaling and autophagy in breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-05-01.
Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma
Authors: Walsh Alice M. , Kapoor Gurpreet S. , Buonato Janine M. , Mathew Lijoy K. , Bi Yingtao , Davuluri Ramana V. , Martinez-Lage Maria , Simon M. Celeste , O'Rourke Donald M. , Lazzara Matthew J. 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen-activated protein kinase (MAPK) to drive cell death in response to inhibitors. Analysis of data from clinical tumor specimens further demonstrated that SPRY2 protein is definitively expressed in GBM tissue, that SPRY2 expression is elevated in GBM tumors expressing EGFR variant III (EGFRvIII), and that elevated SPRY2 mRNA expression portends reduced GBM patient survival. Overall, these results identify SPRY2 and the pathways it regulates as novel candidate biomarkers and therapeutic targets in GBM.
Implications: SPRY2, counter to its roles in other cancer settings, promotes glioma cell and tumor growth and cellular resistance to targeted inhibitors of oncogenic RTKs, thus making SPRY2 and the cell signaling processes it regulates potential novel therapeutic targets in glioma. Mol Cancer Res; 13(8); 1227–37. ©2015 AACR.
miR-19–Mediated Inhibition of Transglutaminase-2 Leads to Enhanced Invasion and Metastasis in Colorectal Cancer
Authors: Cellura D. , Pickard K. , Quaratino S. , Parker H. , Strefford J.C. , Thomas G.J. , Mitter R. , Mirnezami A.H. , Peake N.J. 
Published: May 2015

Abstract
Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells.
Implications: Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2. Mol Cancer Res; 13(7); 1095–105. ©2015 AACR.
Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo
Authors: Steven André , Heiduk Max , Recktenwald Christian V. , Hiebl Bernhard , Wickenhauser Claudia , Massa Chiara , Seliger Barbara 
Published: May 2015

Abstract
Oncogenic transformation is often associated with an increased expression of the cAMP response element binding (CREB) transcription factor controlling the expression of genes involved in cell proliferation, cell cycle, apoptosis, and tumor development, but a link between K-RASV12-induced transformation and CREB has not yet been determined. Therefore, the constitutive and/or inhibitor-regulated mRNA and protein expression of CREB and signal transduction components and growth properties of parental fibroblasts, K-RASV12-transformed counterparts, shCREB K-RASV12 transfectants and human colon carcinoma cells were determined. Increased CREB transcript and protein levels accompanied by an enhanced CREB activity was detected in K-RASV12-transformed murine fibroblasts and K-RASV12-mutated human tumor cells, which is dependent on the MAPK/MEK, PI3K, and/or PKC signal transduction. Immunohistochemical (IHC) staining of colorectal carcinoma lesions and murine tumors, with known KRAS gene mutation status, using antibodies specific for CREB and phospho-CREB, revealed a mechanistic link between CREB expression and K-RASV12-mutated colorectal carcinoma lesions when compared with control tissues. Silencing of CREB by shRNA and/or treatment with a CREB inhibitor (KG-501) reverted the neoplastic phenotype of K-RASV12 transformants as demonstrated by a more fibroblast-like morphology, enhanced apoptosis sensitivity, increased doubling time, decreased migration, invasion and anchorage-independent growth, reduced tumorigenesis, and enhanced immunogenicity in vivo. The impaired shCREB-mediated invasion of K-RASV12 transformants was accompanied by a transcriptional downregulation of different matrix metalloproteinases (MMP) coupled with their reduced enzymatic activity.
Implications: CREB plays a key role in the K-RASV12-mediated neoplastic phenotype and represents a suitable therapeutic target for murine and human K-RASV12-induced tumors. Mol Cancer Res; 13(8); 1248–62. ©2015 AACR.
Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival
Authors: Fisher Matthew L. , Keillor Jeffrey W. , Xu Wen , Eckert Richard L. , Kerr Candace 
Published: May 2015

Abstract
Cancer stem cells are thought to be responsible for rapid tumor growth, metastasis, and enhanced tumor survival following drug treatment. For this reason, there is a major emphasis on identifying proteins that can be targeted to kill cancer stem cells or control their growth, and transglutaminase type II (TGM2/TG2) is such a target in epidermal squamous cell carcinoma. TG2 was originally described as a transamidase in the extracellular matrix that crosslinks proteins by catalyzing ϵ-(γ-glutamyl)lysine bonds. However, subsequent studies have shown that TG2 is a GTP-binding protein that plays an important role in cell signaling and survival. In the present study, TG2 shows promise as a target for anticancer stem cell therapy in human squamous cell carcinoma. TG2 was determined to be highly elevated in epidermal cancer stem cells (ECS cells), and TG2 knockdown or suppression of TG2 function with inhibitors reduced ECS cell survival, spheroid formation, Matrigel invasion, and migration. The reduction in survival is associated with activation of apoptosis. Mechanistic studies, using TG2 mutants, revealed that the GTP-binding activity is required for maintenance of ECS cell growth and survival, and that the action of TG2 in ECS cells is not mediated by NF-κB signaling.
Implications: This study suggests that TG2 has an important role in maintaining cancer stem cell survival, invasive, and metastatic behavior and is an important therapeutic target to reduce survival of cancer stem cells in epidermal squamous cell carcinoma. Mol Cancer Res; 13(7); 1083–94. ©2015 AACR.
Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis
Authors: Cheasley Dane , Pereira Lloyd , Sampurno Shienny , Sieber Oliver , Jorissen Robert , Xu Huiling , Germann Markus , Yuqian Yan , Ramsay Robert G. , Malaterre Jordane 
Published: May 2015

Abstract
Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (MybPlt4) were examined, it was noted that Cyclin E1 (Ccne1) expression was reduced. Furthermore, the induction of Ccne1 in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated Ccne1 and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1–driven tumor growth. Here, it was found that Myb/MYB and Ccne1/CCNE1 expressions were coupled in both mouse and human adenomas. In addition, the low molecular weight Cyclin E1 was the predominant form in intestinal crypts and adenomatous polyposis coli (Apc)–mutant adenomas. Chromatin immunoprecipitation (ChIP) analysis confirmed that Myb bound directly to the Ccne1 promoter and regulated its endogenous expression. In contrast, MybPlt4 served as a dominant-negative factor that inhibited wild-type Myb and this was not apparently compensated for by the transcription factor E2F1 in intestinal epithelial cells. MybPlt4/Plt4 mice died prematurely on an ApcMin/+ background associated with hematopoietic defects, including a myelodysplasia; nevertheless, ApcMin/+ mice were protected from intestinal tumorigenesis when crossed to MybPlt4/+ mice. Knockdown of CCNE1 transcript in murine colorectal cancer cells stabilized chromosome ploidy and decreased tumor formation. These data suggest that Cyclin E1 expression is Myb dependent in normal and transformed intestinal epithelial cells, consistent with a cell-cycle progression and chromosome instability role in cancer.
Implications: This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis. Mol Cancer Res; 13(8); 1185–96. ©2015 AACR.
HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis
Authors: Janeckova Lucie , Pospichalova Vendula , Fafilek Bohumil , Vojtechova Martina , Tureckova Jolana , Dobes Jan , Dubuissez Marion , Leprince Dominique , Baloghova Nikol , Horazna Monika , Hlavata Adela , Stancikova Jitka , Sloncova Eva , Galuskova Katerina , Strnad Hynek , Korinek Vladimir 
Published: May 2015

Abstract
Hypermethylated in cancer 1 (HIC1) represents a prototypic tumor suppressor gene frequently inactivated by DNA methylation in many types of solid tumors. The gene encodes a sequence-specific transcriptional repressor controlling expression of several genes involved in cell cycle or stress control. In this study, a Hic1 allele was conditionally deleted, using a Cre/loxP system, to identify genes influenced by the loss of Hic1. One of the transcripts upregulated upon Hic1 ablation is the toll-like receptor 2 (TLR2). Tlr2 expression levels increased in Hic1-deficient mouse embryonic fibroblasts (MEF) and cultured intestinal organoids or in human cells upon HIC1 knockdown. In addition, HIC1 associated with the TLR2 gene regulatory elements, as detected by chromatin immunoprecipitation, indicating that Tlr2 indeed represents a direct Hic1 target. The Tlr2 receptor senses “danger” signals of microbial or endogenous origin to trigger multiple signaling pathways, including NF-κB signaling. Interestingly, Hic1 deficiency promoted NF-κB pathway activity not only in cells stimulated with Tlr2 ligand, but also in cells treated with NF-κB activators that stimulate different surface receptors. In the intestine, Hic1 is mainly expressed in differentiated epithelial cells and its ablation leads to increased Tlr2 production. Finally, in a chemical-induced mouse model of carcinogenesis, Hic1 absence resulted in larger Tlr2-positive colonic tumors that showed increased proportion of proliferating cells.
Implications: The tumor-suppressive function of Hic1 in colon is related to its inhibitory action on proproliferative signaling mediated by the Tlr2 receptor present on tumor cells. Mol Cancer Res; 13(7); 1139–48. ©2015 AACR.