bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the BCL2 Promoter in Response to Hedgehog/GLI Signal Transduction Is Predominantly Mediated by GLI2
Authors: Regl Gerhard , Kasper Maria , Schnidar Harald , Eichberger Thomas , Neill Graham W. , Philpott Michael P. , Esterbauer Harald , Hauser-Kronberger Cornelia , Frischauf Anna-Maria , Aberger Fritz 
Published: September 2005

Abstract
Aberrant activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of basal cell carcinoma (BCC). The zinc finger transcription factors GLI1 and GLI2 are considered mediators of the HH signal in epidermal cells, although their tumorigenic nature and their relative contribution to tumorigenesis are only poorly understood. To shed light on the respective role of these transcription factors in epidermal neoplasia, we screened for genes preferentially regulated either by GLI1 or GLI2 in human epidermal cells. We show here that expression of the key antiapoptotic factor BCL2 is predominantly activated by GLI2 compared with GLI1. Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region. We found that one of these binding sites is critical for conferring GLI2-specific activation of the human BCL2 promoter and that the selective induction of BCL2 expression depends on the zinc finger DNA binding domain of GLI2. In vivo, GLI2 and BCL2 were coexpressed in the outer root sheath of hair follicles and BCC and in plasma cells that infiltrated BCC tumor islands. On the basis of the latter observation, we analyzed plasma cell-derived tumors and found strong expression of GLI2 and BCL2 in neoplastic cells of plasmacytoma patients, implicating HH/GLI signaling in the development of plasma cell-derived malignancies. The results reveal a central role for GLI2 in activating the prosurvival factor BCL2, which may represent an important mechanism in the development or maintenance of cancers associated with inappropriate HH signaling.
Activating Fc Receptors Are Required for Antitumor Efficacy of the Antibodies Directed toward CD25 in a Murine Model of Adult T-Cell Leukemia
Authors: Zhang Meili , Zhang Zhuo , Garmestani Kayhan , Goldman Carolyn K. , Ravetch Jeffrey V. , Brechbiel Martin W. , Carrasquillo Jorge A. , Waldmann Thomas A. 
Published: September 2005

AbstractWe previously showed therapeutic efficacy of humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6 monoclonal antibodies, which recognize CD25, for human adult T-cell leukemia (ATL) in a murine model. In this study, we investigated the mechanism underlying the tumor-killing action mediated by these antibodies on an ATL model in nonobese diabetic/severe combined immunodeficient (SCID/NOD) wild-type mice that lack effective T and natural killer (NK) cells and in SCID/NOD Fc receptor common γ chain knockout (FcRγ−/−) mice. The ATL model was established by i.p. injection of human ATL cells (MET-1) into SCID/NOD wild-type or SCID/NOD FcRγ−/− mice. HAT, MAT, and 7G7/B6 were given to the leukemia-bearing mice at a dose of 100 μg weekly for 4 weeks. The three antibodies inhibited the leukemia growth significantly in SCID/NOD wild-type mice, as monitored by serum levels of human β2-microglobulin (P &lt; 0.01), and prolonged survival of the leukemia-bearing SCID/NOD wild-type mice (P &lt; 0.01) as compared with the control group. However, none of the antibodies manifested efficacy on the leukemia growth and survival of the SCID/NOD FcRγ−/− mice bearing MET-1 leukemia. In a pharmacokinetics study, the blood concentrations of the radiolabeled antibodies decreased with time similarly in SCID/NOD wild-type and SCID/NOD FcRγ−/− mice. Although NK cells may play a role in humans, in this murine model FcRγ receptors on non-NK cells, such as polymorphonuclear leukocytes or monocytes, are required for the tumor-killing action of the antibodies directed toward CD25.
Direct Assessment of Drug Penetration into Tissue Using a Novel Application of Three-Dimensional Cell Culture
Authors: Kyle Alastair H. , Huxham Lynsey A. , Chiam Aaron S. J. , Sim David H. , Minchinton Andrew I. 
Published: September 2005

Abstract
The failure of many anticancer drugs to control growth of solid cancers may stem in part from inadequate delivery to tumor regions distant from vasculature. Although the identification of new anticancer drug targets has led to the development of many new drug candidates, there is a lack of methodology for identifying drugs that adequately penetrate tumor tissue. We have developed a novel multilayered cell culture-based assay, which detects the penetration of anticancer drugs based on their effect within tissue. Drug exposures are made over 1 hour to one side of a disk of tissue ∼150-μm thick, with the other side temporarily closed off, and penetration is then assessed 1–3 days later via bromodeoxyuridine-based detection of S-phase cells. Using this assay, the tissue distribution of a selection of anthracycline analogues was assessed. At clinically relevant exposures, none of the agents were able to affect cells on the far side of the culture at levels approaching that seen on the near (exposed) side. Doxorubicin and epirubicin exhibited ∼10-fold decreases in the drug exposure seen by the cells on the far side relative to those on the near side of the cultures, whereas for daunorubicin and mitoxantrone, ∼30-fold and &gt;30-fold decreases were observed respectively. Results were consistent with the observed gradients in drug-derived fluorescence of doxorubicin, epirubicin, and daunorubicin. This model could be applied as a simple anticancer drug development screen to discover drugs that exhibit desirable penetration properties.
BRCA1 Induces Antioxidant Gene Expression and Resistance to Oxidative Stress
Authors: Bae Insoo , Fan Saijun , Meng Qinghui , Rih Jeong Keun , Kim Hee Jong , Kang Hyo Jin , Xu Jingwen , Goldberg Itzhak D. , Jaiswal Anil K. , Rosen Eliot M. 
Published: September 2005

Abstract
Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.
Down-Regulation of the Homeodomain Factor Cdx2 in Colorectal Cancer by Collagen Type I
Authors: Brabletz Thomas , Spaderna Simone , Kolb Jochen , Hlubek Falk , Faller Gerhard , Bruns Christiane J. , Jung Andreas , Nentwich Jens , Duluc Isabelle , Domon-Dell Claire , Kirchner Thomas , Freund Jean-Noel 
Published: September 2005

Abstract
The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein β-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through β1 integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.
Gonadotropin-Releasing Hormone Induces Apoptosis of Prostate Cancer Cells
Authors: Kraus Sarah , Levy Gal , Hanoch Tamar , Naor Zvi , Seger Rony 
Published: September 2005

Abstract
A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH2-terminal kinase (JNK) and inhibited by the phosphatidylinositol 3′-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src- and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.
Mutations of PIK3CA in Anaplastic Oligodendrogliomas, High-Grade Astrocytomas, and Medulloblastomas
Authors: Broderick Daniel K. , Di Chunhui , Parrett Timothy J. , Samuels Yardena R. , Cummins Jordan M. , McLendon Roger E. , Fults Daniel W. , Velculescu Victor E. , Bigner Darell D. , Yan Hai 
Published: September 2005

Abstract
The phosphatidylinositol 3′-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the PTEN tumor suppressor gene. Recently, mutations in PIK3CA, a member of the family of phosphatidylinositol 3′-kinase catalytic subunits, were identified in a significant fraction (25–30%) of colorectal cancers, gastric cancers, and glioblastomas and in a smaller fraction of breast and lung cancers. These mutations were found to cluster into two major “hot spots” located in the helical and catalytic domains. To determine whether PIK3CA is genetically altered in brain tumors, we performed a large-scale mutational analysis of the helical and catalytic domains. A total of 13 mutations of PIK3CA within these specific domains were identified in anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas, whereas no mutations were identified in ependymomas or low-grade astrocytomas. These observations implicate PIK3CA as an oncogene in a wider spectrum of adult and pediatric brain tumors and suggest that PIK3CA may be a useful diagnostic marker or a therapeutic target in these cancers.
Ether à go-go Potassium Channels as Human Cervical Cancer Markers
Authors: Farias Luz María Barajas , Ocaña Deysi Bermúdez , Díaz Lorenza , Larrea Fernando , Avila-Chávez Euclides , Cadena Adriana , Hinojosa Luz María , Lara Gerardo , Villanueva Luis Alberto , Vargas Carlos , Hernández-Gallegos Elizabeth , Camacho-Arroyo Ignacio , Dueñas-González Alfonso , Pérez-Cárdenas Enrique , Pardo Luis A. , Morales Angélica , Taja-Chayeb Lucía , Escamilla Juan , Sánchez-Peña Carmen , Camacho Javier 
Published: September 2005

Abstract
Ether à go-go (EAG) potassium channels display oncogenic properties. In normal tissues, EAG mRNA is almost exclusively expressed in brain, but it is expressed in several somatic cancer cell lines, including HeLa, from cervix. Antisense experiments against eag reduce cell proliferation in some cancer cell lines, and inhibition of EAG-mediated currents has been suggested to decrease cell proliferation in a melanoma cell line. Because of the potential clinical relevance of EAG, we investigated EAG mRNA expression in the following fresh samples from human uterine cervix: 5 primary cultures obtained from cancerous biopsies, 1 cancerous fresh tissue, and 12 biopsies of control normal tissue. All of the control cervical samples came from patients with negative pap smears. Reverse transcription-PCR and Southern-blot experiments revealed eag expression in 100% of the cancerous samples and in 33% of the normal biopsies. Immunochemistry experiments showed the presence of EAG channel protein in cells from the primary cultures and in cervical cancer biopsies sections from the same patients. In addition, we looked for EAG-mediated currents in the cultures from cervical cancer cells. Here we show for the first time EAG channel activity in human tumors. Patch-clamp recordings showed typical EAG-mediated currents modulated by magnesium and displaying a pronounced Cole-Moore shift. Because EAG expression and channel activity have been suggested to be important in cell proliferation, our findings strongly support the idea of considering EAG as a tumor marker as well as a potential membrane therapeutic target for cervical cancer.
The Ras/Mitogen-Activated Protein Kinase Pathway Inhibitor and Likely Tumor Suppressor Proteins, Sprouty 1 and Sprouty 2 Are Deregulated in Breast Cancer
Authors: Lo Ting Ling , Yusoff Permeen , Fong Chee Wai , Guo Ke , McCaw Ben J. , Phillips Wayne A. , Yang He , Wong Esther Sook Miin , Leong Hwei Fen , Zeng Qi , Putti Thomas Choudary , Guy Graeme R. 
Published: September 2005

Abstract
Sprouty (Spry) proteins were found to be endogenous inhibitors of the Ras/mitogen-activated protein kinase pathway that play an important role in the remodeling of branching tissues. We investigated Spry expression levels in various cancers and found that Spry1 and Spry2 were down-regulated consistently in breast cancers. Such prevalent patterns of down-regulation may herald the later application of these isoforms as tumor markers that are breast cancer specific and more profound than currently characterized markers. Spry1 and 2 were expressed specifically in the luminal epithelial cells of breast ducts, with higher expression during stages of tissue remodeling when the epithelial ducts are forming and branching. These findings suggest that Sprys might be involved as a modeling counterbalance and surveillance against inappropriate epithelial expansion. The abrogation of endogenous Spry activity in MCF-7 cells by the overexpression of a previously characterized dominant-negative mutant of Spry, hSpry2Y55F resulted in enhanced cell proliferation in vitro. The hSpry2Y55F stably expressing cells also formed larger and greater number of colonies in the soft-agar assay. An in vivo nude mice assay showed a dramatic increase in the tumorigenic potential of hSpry2Y55F stable cells. The consistent down-regulation of Spry1 and 2 in breast cancer and the experimental evidence using a dominant-negative hSpry2Y55F indicate that Spry proteins may actively maintain tissue integrity that runs amok when their expression is decreased below normal threshold levels. This alludes to a previously unrecognized role for Sprys in cancer development.
Cyclooxygenase-2 Modulates the Insulin-Like Growth Factor Axis in Non–Small-Cell Lung Cancer
Authors: Põld Mehis , Krysan Kostyantyn , Põld Anu , Dohadwala Mariam , Heuze-Vourc’h Nathalie , Mao Jenny T. , Riedl Karen L. , Sharma Sherven , Dubinett Steven M. 
Published: September 2005

Abstract
Constitutive overexpression of cyclooxygenase-2 (COX-2) occurs frequently in several different malignancies, including lung, colon, breast, and prostate cancer. Clinical studies have established elevated serum insulin-like growth factor (IGF-I) content and IGF-I:IGF-binding protein 3 (IGFBP-3) ratio as risk factors for these same malignancies. Therefore, we sought to determine the link between COX-2 expression and the IGF axis in COX-2 gene-modified human non–small-cell lung cancer (NSCLC) cells. Overexpression of COX-2 in NSCLC cells enhanced the antiapoptotic and mitogenic effects of IGF-I and IGF-II, facilitated the autophosphorylation of the type 1 IGF receptor, increased class IA phosphatidylinositol 3′-kinase activity, and decreased expression of IGFBP-3. Thus, these findings show that COX-2 augments the stimulatory arm of the IGF axis.
Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C
Authors: Ruiz Christian , Huang Wentao , Hegi Monika E. , Lange Katrin , Hamou Marie-France , Fluri Erika , Oakeley Edward J. , Chiquet-Ehrismann Ruth , Orend Gertraud 
Published: September 2005

Abstract
Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of β-catenin and stimulated the expression of the β-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.
Estrogen Receptor Genotypes and Haplotypes Associated with Breast Cancer Risk
Authors: Gold Bert , Kalush Francis , Bergeron Julie , Scott Kevin , Mitra Nandita , Wilson Kelly , Ellis Nathan , Huang Helen , Chen Michael , Lippert Ross , Halldorsson Bjarni V. , Woodworth Beth , White Thomas , Clark Andrew G. , Parl Fritz F. , Broder Samuel , Dean Michael , Offit Kenneth 
Published: September 2005

Abstract
Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), ∼ O.4; 95% confidence interval (CI), 0.2–0.8; P &lt; 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2–3.8; P &lt; 0.05). A unique risk haplotype was present in ∼7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2–2.4; P &lt; 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.
Differential Transplantability of Tumor-Associated Stromal Cells
Authors: Duda Dan G. , Fukumura Dai , Munn Lance L. , Booth Michael F. , Brown Edward B. , Huang Peigen , Seed Brian , Jain Rakesh K. 
Published: September 2005

Abstract
At the time of transplantation, tumor fragments contain “passenger” cells: endothelial cells and other stromal cells from the original host. Here, we investigated the fate of genetically labeled endothelial and nonendothelial stromal cells after transplantation in syngeneic mice. We report that angiogenic stroma associated with tumor or adipose tissue persists when transplanted, remains functional, and governs the initial neovascularization of grafted tissue fragments for more than 4 weeks after implantation. Surprisingly, the passenger endothelial cells survive longer than other stromal cells, which are replaced by host-activated fibroblasts after 3 weeks. The transplantability of tumor stroma suggests that the angiogenic potential of a tumor xenograft, which determines its viability, depends on the presence of passenger endothelial cells and other stromal cells within the xenograft. These studies of tumor tissue transplantation provide a platform for exploring the role of epithelial–stromal interactions in studies of tumor heterogeneity and drug resistance.