bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pierce1, a Novel p53 Target Gene Contributing to the Ultraviolet-Induced DNA Damage Response
Authors: Sung Young Hoon , Kim Hye Jin , Devkota Sushil , Roh Jusik , Lee Jaehoon , Rhee Kunsoo , Bahk Young Yil , Lee Han-Woong 
Published: December 2010

AbstractRetinoblastoma (Rb) and p53 genes are mutated or inactivated in most human cancers and mutually regulate each other. Recently, we reported that expression of diverse genes was altered in Rb-deficient mouse embryonic fibroblasts (MEF). In this study, we found that Pierce1, a novel transcript upregulated in Rb-deficient MEFs, is a transcriptional target of p53. Although Pierce1 promoter did not respond to the ectopic expression of E2F1, it was strongly activated by p53 via 2 cis-elements. Consistently, the expression of Pierce1 was induced by genotoxic stresses that activate p53 but was not detected in p53-deficient MEFs. Pierce1 was posttranslationally stabilized by ultraviolet C (UVC) irradiation, and UVC-activated ATR (ataxia telangiectasia-mutated and Rad3-related) signaling suppressed proteosomal degradation of Pierce1 protein. Furthermore, knockdown of Pierce1 compromised the checkpoint response of wild-type MEFs to UVC irradiation, accompanying the diminished expression of p53 target genes. Together, our data suggest that Pierce1 is an important p53 target gene contributing to normal DNA damage response and may play crucial roles in maintaining genomic integrity against genotoxic stresses, including UVC irradiation. Cancer Res; 70(24); 10454–63. ©2010 AACR.
HIF-2α Enhances β-Catenin/TCF-Driven Transcription by Interacting with β-Catenin
Authors: Choi Hyunsung , Chun Yang-Sook , Kim Tae-You , Park Jong-Wan 
Published: December 2010

Abstract
The tumor-promoting factors β-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1α negatively regulates Wnt/β-catenin signaling by sequestering β-catenin from β-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2α in β-catenin regulation. In this study, it was found that, like HIF-1α, HIF-2α interacts with β-catenin, but at a different site. Furthermore, HIF-2α was found to assemble with β-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2α promote p300 coactivator recruitment by β-catenin. Furthermore, HIF-2α and β-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2α was found to be required for β-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2α and β-catenin. Interestingly, these actions of HIF-2α oppose those of HIF-1α on β-catenin and cell growth, and this suggests that HIF-1α/HIF-2α balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist. Cancer Res; 70(24); 10101–11. ©2010 AACR.
The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
Authors: Liu Manran , Sakamaki Toshiyuki , Casimiro Mathew C. , Willmarth Nicole E. , Quong Andrew A. , Ju Xiaoming , Ojeifo John , Jiao Xuanmao , Yeow Wen-Shuz , Katiyar Sanjay , Shirley L. Andrew , Joyce David , Lisanti Michael P. , Albanese Christopher , Pestell Richard G. 
Published: December 2010

Abstract
The role of mammary epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor stem cell pathways. IκBαSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB–dependent mammary tumorigenesis. Cancer Res; 70(24); 10464–73. ©2010 AACR.
Human Bone Marrow–Derived MSCs Can Home to Orthotopic Breast Cancer Tumors and Promote Bone Metastasis
Authors: Goldstein Robert H. , Reagan Michaela R. , Anderson Kristen , Kaplan David L. , Rosenblatt Michael 
Published: December 2010

Abstract
American women have a nearly 25% lifetime risk of developing breast cancer, with 20% to 40% of these patients developing life-threatening metastases. More than 70% of patients presenting with metastases have skeletal involvement, which signals progression to an incurable stage. Tumor–stroma cell interactions are only superficially understood, specifically regarding the ability of stromal cells to affect metastasis. In vivo models show that exogenously supplied human bone marrow–derived stem cells (hBMSC) migrate to breast cancer tumors, but no reports have shown endogenous hBMSC migration from the bone to primary tumors. Here, we present a model of in vivo hBMSC migration from a physiologic human bone environment to human breast tumors. Furthermore, hBMSCs alter tumor growth and bone metastasis frequency. These may home to certain breast tumors based on tumor-derived TGF-β1. Moreover, at the primary tumor level, interleukin 17B (IL-17B)/IL-17BR signaling may mediate interactions between hBMSCs and breast cancer cells. Cancer Res; 70(24); 10044–50. ©2010 AACR.
Paxillin Predicts Survival and Relapse in Non–Small Cell Lung Cancer by MicroRNA-218 Targeting
Authors: Wu De-Wei , Cheng Ya-Wen , Wang John , Chen Chih-Yi , Lee Huei 
Published: December 2010

AbstractPaxillin (PXN) gene mutations are associated with lung adenocarcinoma progression and PXN is known to be a target gene of microRNA-218 (miR-218). On this basis, we hypothesized that PXN overexpression via miR-218 suppression may promote tumor progression and metastasis and that PXN may predict survival and relapse in non–small cell lung cancer (NSCLC). Expression of miR-218 and PXN in 124 surgically resected lung tumors were evaluated by real-time PCR and immunohistochemical analysis. The prognostic value of miR-218 and PXN expression on overall survival (OS) and relapse-free survival (RFS) was analyzed by the Kaplan–Meier test and Cox regression analysis. miR-218 expression in lung tumors was negatively associated with PXN expression. Multivariate analyses showed that PXN and miR-218 might independently predict OS and RFS, respectively, in NSCLC. Moreover, patients with low miR-218 combined with PXN-positive had the worst OS and RFS among the 4 combinations. In a cell model, PXN was negatively regulated by miR-218 and cell proliferation, invasion, and soft agar colony formation were enhanced by PXN overexpression induced by miR-218 suppression. Taken together, our findings suggest that PXN overexpression induced by miR-218 suppression is an independent predictor of survival and relapse in NSCLC, highlighting PXN as a potential therapeutic target to improve clinical outcomes in this disease. Cancer Res; 70(24); 10392–401. ©2010 AACR.
Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations
Authors: Okamoto Kunio , Okamoto Isamu , Okamoto Wataru , Tanaka Kaoru , Takezawa Ken , Kuwata Kiyoko , Yamaguchi Haruka , Nishio Kazuto , Nakagawa Kazuhiko 
Published: December 2010

Abstract
The molecular mechanism by which epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non–small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation–positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation–positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI–induced apoptotic death in these cells. Cancer Res; 70(24); 10402–10. ©2010 AACR.
Conditional Deletion of the Focal Adhesion Kinase FAK Alters Remodeling of the Blood–Brain Barrier in Glioma
Authors: Lee Jisook , Borboa Alexandra K. , Chun Hyun Bae , Baird Andrew , Eliceiri Brian P. 
Published: December 2010

Abstract
Gliomas generally infiltrate the surrounding normal brain parenchyma, a process associated with increased vascular permeability (VP) and dysregulation of the blood–brain barrier (BBB). However, the molecular mechanisms underlying glioma-induced VP in the brain remain poorly understood. Using a conditional, endothelium-specific deletion of the focal adhesion kinase (FAK) in the mouse (FAK CKO), we show that FAK is critical for destabilization of the tumor endothelium in tumor-bearing mice, with mutant mice exhibiting a relatively normalized vasculature compared with wild-type mice (FAK WT). Tumor vessels in the FAK CKO mice displayed reduced VP compared with FAK WT mice, resulting in reduced tumor growth. Additionally, FAK CKO mice displayed partial restoration of cell–cell junction proteins in the tumor vessels and astrocyte–endothelium interactions in tumors, revealing an additional role of astrocytes in mediating tumor-induced VP. Together, these results provide genetic evidence that FAK is a mediator of tumor-induced VP in the brain. Our findings may help understand how therapeutics might be used to regulate specific cell-type interactions to restore BBB structure/function in cancer and perhaps other pathologic conditions. Cancer Res; 70(24); 10131–40. ©2010 AACR.
RETRACTED: Loss of Metallothionein Predisposes Mice to Diethylnitrosamine-Induced Hepatocarcinogenesis by Activating NF-κB Target Genes
Authors: Majumder Sarmila , Roy Satavisha , Kaffenberger Thomas , Wang Bo , Costinean Stefan , Frankel Wendy , Bratasz Anna , Kuppusamy Periannan , Hai Tsonwin , Ghoshal Kalpana , Jacob Samson T. 
Published: December 2010

Abstract
Metallothioneins (MT) are potent scavengers of free radicals that are silenced in primary hepatocellular carcinomas (HCC) of human and rodent origin. To examine whether loss of MT promotes hepatocarcinogenesis, male Mt-1 and Mt-2 double knockout (MTKO) and wild-type (WT) mice were exposed to diethylnitrosamine (DEN) and induction of HCC was monitored at 23 and 33 weeks. The size and number of liver tumors, the ratio between liver and body weight, and liver damage were markedly elevated in the MTKO mice at both time points compared with the WT mice. At 23 weeks, MTKO mice developed HCC whereas WT mice developed only preneoplastic nodules suggesting that loss of MT accelerates hepatocarcinogenesis. MTKO tumors also exhibited higher superoxide anion levels. Although NF-κB activity increased in the liver nuclear extracts of both genotypes after DEN exposure, the complex formed in MTKO mice was predominantly p50/65 heterodimer (transcriptional activator) as opposed to p50 homodimer (transcriptional repressor) in WT mice. Phosphorylation of p65 at Ser276 causing its activation was also significantly augmented in DEN-exposed MTKO livers. NF-κB targets that include early growth response genes and proinflammatory cytokines were significantly upregulated in MTKO mice. Concurrently, there was a remarkable increase (∼100-fold) in Pai-1 expression; significant increase in c-Jun, c-Fos, c-Myc, Ets2, and ATF3 expressions; and growth factor signaling that probably contributed to the increased tumor growth in MTKO mice. Taken together, these results demonstrate that MTs protect mice from hepatocarcinogen-induced liver damage and carcinogenesis, underscoring their potential therapeutic application against hepatocellular cancer. Cancer Res; 70(24); 10265–76. ©2010 AACR.
Tip30 Deletion in MMTV-Neu Mice Leads to Enhanced EGFR Signaling and Development of Estrogen Receptor–Positive and Progesterone Receptor–Negative Mammary Tumors
Authors: Zhang Chengliang , Mori Mikito , Gao Shenglan , Li Aimin , Hoshino Isamu , Aupperlee Mark D. , Haslam Sandra Z. , Xiao Hua 
Published: December 2010

Abstract
Estrogen receptor–positive and progesterone receptor–negative (ER+/PR−) breast cancers account for 15% to 25% of all human breast cancers and display more aggressive malignant characteristics than ER+/PR+ cancers. However, the molecular mechanism underlying development of ER+/PR− breast cancers still remains elusive. We show here that Tip30 deletion dramatically accelerated the onset of mammary tumors in the MMTV-Neu mouse model of breast cancer. The mammary tumors arising in Tip30−/−/MMTV-Neu mice were exclusively ER+/PR−. The growth of these ER+/PR− tumors depends not only on estrogen but also on progesterone despite the absence of detectable PR. Tip30 is predominantly expressed in ER+ mammary epithelial cells, and its deletion leads to an increase in the number of phospho-ERα–positive cells in mammary glands and accelerated activation of Akt in MMTV-Neu mice. Moreover, we found that Tip30 regulates the EGFR pathway through controlling endocytic downregulation of EGFR protein level and signaling. Together, these findings suggest a novel mechanism in which loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling, leading to the development of ER+/PR− mammary tumors. Cancer Res; 70(24); 10224–33. ©2010 AACR.
Antagonism of Cytotoxic Chemotherapy in Neuroblastoma Cell Lines by 13-cis-Retinoic Acid Is Mediated by the Antiapoptotic Bcl-2 Family Proteins
Authors: Hadjidaniel Michael D. , Reynolds C. Patrick 
Published: December 2010

Abstract
13-cis-Retinoic acid (13-cis-RA) is given at completion of cytotoxic therapy to control minimal residual disease in neuroblastoma. We investigated the effect of combining 13-cis-RA with cytotoxic agents employed in neuroblastoma therapy using a panel of 6 neuroblastoma cell lines. The effect of 13-cis-RA on the mitochondrial apoptotic pathway was studied by flow cytometry, cytotoxicity by DIMSCAN, and protein expression by immunoblotting. Pretreatment and direct combination of 13-cis-RA with etoposide, topotecan, cisplatin, melphalan, or doxorubicin markedly antagonized the cytotoxicity of those agents in 4 out of 6 tested neuroblastoma cell lines, increasing fractional cell survival by 1 to 3 logs. The inhibitory concentration of drugs (IC99) increased from clinically achievable levels to nonachievable levels, greater than 5-fold (cisplatin) to greater than 7-fold (etoposide). In SMS-KNCR neuroblastoma cells, 13-cis-RA upregulated expression of Bcl-2 and Bcl-xL RNA and protein, and this was associated with protection from etoposide-mediated apoptosis at the mitochondrial level. A small molecule inhibitor of the Bcl-2 family of proteins (ABT-737) restored mitochondrial membrane potential loss and apoptosis in response to cytotoxic agents in 13-cis-RA treated cells. Prior selection for resistance to RA did not diminish the response to cytotoxic treatment. Thus, combining 13-cis-RA with cytotoxic chemotherapy significantly reduced the cytotoxicity for neuroblastoma in vitro, mediated at least in part via the antiapoptotic Bcl-2 family of proteins. Mol Cancer Ther; 9(12); 3164–74. ©2010 AACR.
Phase I Clinical Trial of MPC-6827 (Azixa), a Microtubule Destabilizing Agent, in Patients with Advanced Cancer
Authors: Tsimberidou Apostolia-Maria , Akerley Wallace , Schabel Matthias C. , Hong David S. , Uehara Cynthia , Chhabra Anil , Warren Terri , Mather Gary G. , Evans Brent A. , Woodland Deane P. , Swabb Edward A. , Kurzrock Razelle 
Published: December 2010

Abstract
MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on β-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m2, with subsequent increments of 0.6 mg/m2 until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1–10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m2 (1/6 patients) and at 4.5 mg/m2 (1/7 patients). The MTD was determined to be 3.3 mg/m2 (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m2 once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing. Mol Cancer Ther; 9(12); 3410–9. ©2010 AACR.
Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation
Authors: Rho Jin Kyung , Choi Yun Jung , Jeon Byung-Suk , Choi Su Jin , Cheon Gi Jeong , Woo Sang-Keun , Kim Hye-Ryoun , Kim Cheol Hyeon , Choi Chang-Min , Lee Jae Cheol 
Published: December 2010

Abstract
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) produce an initially dramatic response in lung cancer patients harboring a mutation in the EGFR gene, development of acquired resistance is almost inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. This study investigated whether the addition of silibinin to therapy with gefitinib or erlotinib could overcome T790M-mediated drug resistance considering that silibinin has various antitumor effects, including EGFR modulation. Silibinin selectively reduced the activity of the EGFR family (EGFR, ErbB2, and ErbB3) through the inhibition of receptor dimerization in lung cancer cells with EGFR mutations, but not in those harboring the wild type. In primary and acquired resistant cells with T790M, addition of silibinin enhanced the ability of EGFR-TKIs to downregulate EGFR signals and to inhibit cell growth. Similarly, the combination of silibinin and erlotinib effectively suppressed tumor growth in erlotinib resistance-bearing PC-9 xenografts. The results indicate that the addition of silibinin to EGFR-TKIs is a promising strategy to overcome T790M-mediated drug resistance. Mol Cancer Ther; 9(12); 3233–43. ©2010 AACR.
Genome-Wide mRNA and microRNA Profiling of the NCI 60 Cell-Line Screen and Comparison of FdUMP[10] with Fluorouracil, Floxuridine, and Topoisomerase 1 Poisons
Authors: Gmeiner William H. , Reinhold William C. , Pommier Yves 
Published: December 2010

Abstract
A profile of microRNA (miRNA) and mRNA expression patterns across the NCI-60 cell-line screen was analyzed to identify expression signatures that correlate with sensitivity to FdUMP[10], fluorouracil (5FU), floxuridine (FdU), topotecan, and irinotecan. Genome-wide profile analyses revealed FdUMP[10] resembles FdU most closely and shows dissimilarities with 5FU. FdUMP[10] had the largest dynamic range of any of these drugs across the NCI-60 indicative of cancer cell–specific activity. Genes involved in endocytosis, such as clathrin (CLTC), SNF8, annexin A6 (ANXA6), and amyloid protein-binding 2 (APPBP2) uniquely correlated with sensitivity to FdUMP[10], consistent with a protein-mediated cellular uptake of FdUMP[10]. Genes involved in nucleotide metabolism were enriched for the three fluoropyrimidine drugs, with the expression profile for 5FU correlated to an RNA-mediated cytotoxic mechanism, whereas expression of glycosyltransferases (XYLT2) that use UDP sugars as substrates and the nucleoside diphosphatase and metastasis suppressor NM23 (NME1) were associated with FdUMP[10] sensitivity. Topotecan and irinotecan had significant negative correlations with miR-24, a miRNA with a high aggregate PCT score for topoisomerase 1 (Top1). Our results reveal significant new correlations between FdUMP[10] and Top1 poisons, as well as new information on the unique cytotoxic mechanism and genomic signature of FdUMP[10]. Mol Cancer Ther; 9(12); 3105–14. ©2010 AACR.
Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized 13C Magnetic Resonance Spectroscopy
Authors: Bohndiek Sarah E. , Kettunen Mikko I. , Hu De-en , Witney Timothy H. , Kennedy Brett W.C. , Gallagher Ferdia A. , Brindle Kevin M. 
Published: December 2010

Abstract
Nuclear spin hyperpolarization can dramatically increase the sensitivity of the 13C magnetic resonance experiment, allowing dynamic measurements of the metabolism of hyperpolarized 13C-labeled substrates in vivo. Here, we report a preclinical study of the response of lymphoma tumors to the vascular disrupting agent (VDA), combretastatin-A4-phosphate (CA4P), as detected by measuring changes in tumor metabolism of hyperpolarized [1-13C]pyruvate and [1,4-13C2]fumarate. These measurements were compared with dynamic contrast agent–enhanced magnetic resonance imaging (DCE-MRI) measurements of tumor vascular function and diffusion-weighted MRI (DW-MRI) measurements of the tumor cell necrosis that resulted from subsequent loss of tumor perfusion. The rate constant describing flux of hyperpolarized 13C label between [1-13C]pyruvate and lactate was decreased by 34% within 6 hours of CA4P treatment and remained at this lower level at 24 hours. The rate constant describing production of labeled malate from hyperpolarized [1,4-13C2]fumarate increased 1.6-fold and 2.5-fold at 6 and 24 hours after treatment, respectively, and correlated with the degree of necrosis detected in histologic sections. Although DCE-MRI measurements showed a substantial reduction in perfusion at 6 hours after treatment, which had recovered by 24 hours, DW-MRI showed no change in the apparent diffusion coefficient of tumor water at 6 hours after treatment, although there was a 32% increase at 24 hours (P &lt; 0.02) when regions of extensive necrosis were observed by histology. Measurements of hyperpolarized [1-13C]pyruvate and [1,4-13C2]fumarate metabolism may provide, therefore, a more sustained and sensitive indicator of response to a VDA than DCE-MRI or DW-MRI, respectively. Mol Cancer Ther; 9(12); 3278–88. ©2010 AACR.