bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hic-5/ARA55, a LIM Domain–Containing Nuclear Receptor Coactivator Expressed in Prostate Stromal Cells
Authors: Heitzer Marjet D. , DeFranco Donald B. 
Published: July 2006

Abstract
Prostate gland development and growth requires both androgen action and epithelial-stromal communications. In fact, androgen signaling through the androgen receptor (AR) may be important in both stromal and epithelial cells of the prostate. Because interaction of AR with the coactivator, Hic-5/ARA55, results in enhanced androgen-induced transcription, we analyzed Hic-5/ARA55 expression in prostate tissue sections from normal human donors and prostate cancer patients. In each sample, Hic-5/ARA55 expression was confined to the stromal compartment of the prostate. Furthermore, a prostate stromal cell line, WPMY-1 cells, expresses Hic-5/ARA55, which is localized both at focal adhesion complexes and within the soluble cytoplasmic compartment. The ability of Hic-5/ARA55 to shuttle between the nuclear and cytoplasmic compartments was revealed on inhibition of nuclear export with leptomycin B. Small interfering RNA ablation experiments established endogenous Hic-5/ARA55 as a coactivator for both viral and endogenous cellular AR-regulated genes. Finally, the mechanism of Hic-5/ARA55 coactivator activity in WPMY-1 cells was revealed by chromatin immunoprecipitation analysis that showed its androgen-dependent recruitment to the promoter of the stromal androgen-responsive keratinocyte growth factor gene. These data provide the first demonstration of a stromal-specific AR coactivator that has an effect on an androgen-regulated growth factor that is essential for stromal/epithelial cell communication in the prostate. (Cancer Res 2006; 66(14): 7326-33)
SYT-SSX1 and SYT-SSX2 Interfere with Repression of E-Cadherin by Snail and Slug: A Potential Mechanism for Aberrant Mesenchymal to Epithelial Transition in Human Synovial Sarcoma
Authors: Saito Tsuyoshi , Nagai Makoto , Ladanyi Marc 
Published: July 2006

Abstract
Synovial sarcoma is a primitive mesenchymal neoplasm characterized in almost all cases by a t(X;18) fusing the SYT transcriptional coactivator gene with either SSX1 or SSX2, with the resulting fusion gene encoding an aberrant transcriptional regulator. A subset of synovial sarcoma, predominantly cases with the SYT-SSX1 fusion, shows foci of morphologic epithelial differentiation in the form of nests of glandular epithelium. The striking spontaneous mesenchymal to epithelial differentiation in this cancer is reminiscent of a developmental switch, but the only clue to its mechanistic basis has been the observation that most cases of synovial sarcoma with glandular epithelial differentiation (GED) contain SYT-SSX1 instead of SYT-SSX2. We report here that SYT-SSX1 and SYT-SSX2 interact preferentially with Snail or Slug, respectively, and prevent these transcriptional repressors from binding to the proximal E-cadherin promoter as shown by coimmunoprecipitation and chromatin immunoprecipitation. Luciferase reporter assays reveal that SYT-SSX1 and SYT-SSX2 can respectively overcome the Snail- or Slug-mediated repression of E-cadherin transcription. This provides a mechanism by which E-cadherin expression, a prerequisite of epithelial differentiation, is aberrantly derepressed in synovial sarcoma and may also explain the association of GED with the SYT-SSX1 fusion because it interferes with Snail, the stronger repressor of the E-cadherin promoter. Thus, our data provide a mechanistic basis for the observed heterogeneity in the acquisition of epithelial characteristics in synovial sarcoma and highlight the potential role of differential interactions with Snail or Slug in modulating this phenotypic transition. (Cancer Res 2006; 66(14): 6919-27)
E2F-1 Overexpression in U2OS Cells Increases Cyclin B1 Levels and cdc2 Kinase Activity and Sensitizes Cells to Antimitotic Agents
Authors: Russo Angelo J. , Magro Pellegrino G. , Hu Zhen , Li Wei-Wei , Peters Rowayda , Mandola Jennifer , Banerjee Debabrata , Bertino Joseph R. 
Published: July 2006

Abstract
The E2F transcription factors play a critical role in coordinating transcription of specific genes essential for G1-S transition. In early G1, the retinoblastoma protein (pRB) becomes phosphorylated by cyclin-dependent kinases, disrupting pRB binding to E2F-1-3, allowing “free” E2F to regulate genes involved in proliferation. In the present study, we used a tetracycline E2F-1 inducible U2OS osteosarcoma cell line to investigate the effect of increasing levels of E2F-1 on the cytotoxicity of various chemotherapeutic drugs. Upon overexpression of E2F-1, there was no detectable change in cytotoxicity to doxorubicin, cisplatin, 5-fluorouracil, or etoposide. In contrast, overexpression of E2F-1 resulted in a marked increase in sensitivity to vinblastine and paclitaxel, drugs that are known to be more effective against cells in M phase. Therefore, we investigated the effect of E2F-1 overexpression on proteins regulating the G2-M transition and M phase, in particular cyclin B1 and cdc2 kinase. Cyclin B1 mRNA and protein levels increased within 24 hours of E2F1 induction together with an increase in associated cdc2 kinase activity. Overexpression of cyclin B1 also resulted in a specific increase in sensitivity to paclitaxel and an increase in the cellular growth rate. Knockdown of cyclin B1 using an RNA interference oligo resulted in a slower cellular growth rate and an increase in resistance to paclitaxel. These studies add support to recent reports that show E2F regulates genes involved in mitotic entry and exit and allow the suggestion that mitotic inhibitors may have selective effects in tumors that overexpress E2F-1. (Cancer Res 2006; 66(14): 7253-60)
Physical and Functional Interactions between Cas and c-Src Induce Tamoxifen Resistance of Breast Cancer Cells through Pathways Involving Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 5b
Authors: Riggins Rebecca B. , Thomas Keena S. , Ta Huy Q. , Wen Jie , Davis Rebecca J. , Schuh Natasha R. , Donelan Stacey S. , Owen Katherine A. , Gibson Matthew A. , Shupnik Margaret A. , Silva Corinne M. , Parsons Sarah J. , Clarke Robert , Bouton Amy H. 
Published: July 2006

Abstract
High expression of the adaptor molecule Cas has been linked to resistance to the antiestrogen tamoxifen, both in tissue culture and in human tumors. The aim of this study was to elucidate the mechanism(s) by which overexpression of Cas confers resistance to tamoxifen. Cas overexpression in MCF-7 breast cancer cells was shown to alleviate both tamoxifen-mediated growth inhibition and induction of apoptosis. This enhancement of cell proliferation/survival occurred in the absence of detectable effects on estrogen receptor (ER) transcriptional activity under conditions where tamoxifen was present, indicating that Cas-dependent tamoxifen resistance is not the result of a switch to an ER-negative phenotype or enhanced responses to the partial agonist activity of tamoxifen. Instead, we present evidence, suggesting that Cas promotes tamoxifen resistance by deregulation of alternative cell proliferation pathways, particularly those mediated through enhanced c-Src protein tyrosine kinase activity arising from Cas/c-Src interactions. Overexpression of Cas was found to drive endogenous c-Src into complex with Cas, a process that has been shown previously to cause up-regulation of c-Src tyrosine kinase activity. MCF-7 cells overexpressing Cas exhibited increased phosphorylation of two c-Src substrates, Tyr845 in the kinase domain of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription (STAT) 5b. Importantly, Cas-dependent protection from the antiproliferative effects of tamoxifen was reversed by the expression of dominant inhibitory variants of these substrates (Y845F EGFR and COOH-terminally truncated STAT5b). Based on these findings, we suggest that the Cas/c-Src/EGFR/STAT5 signaling axis is a major regulator of tamoxifen-resistant breast cancer cell growth and survival. (Cancer Res 2006; 66(14): 7007-15)
Acting via a Cell Surface Receptor, Thyroid Hormone Is a Growth Factor for Glioma Cells
Authors: Davis Faith B. , Tang Heng-Yuan , Shih Ai , Keating Travis , Lansing Lawrence , Hercbergs Aleck , Fenstermaker Robert A. , Mousa Ahmed , Mousa Shaker A. , Davis Paul J. , Lin Hung-Yun 
Published: July 2006

Abstract
Recent evidence suggests that the thyroid hormone l-thyroxine (T4) stimulates growth of cancer cells via a plasma membrane receptor on integrin αVβ3. The contribution of this recently described receptor for thyroid hormone and receptor-based stimulation of cellular mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] activity, to enhancement of cell proliferation by thyroid hormone was quantitated functionally and by immunologic means in three glioma cell lines exposed to T4. At concentrations of 1 to 100 nmol/L, T4 caused proliferation of C6, F98, and GL261 cells, measured by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation. This effect was inhibited by the T4 analogue, tetraiodothyroacetic acid, and by an αVβ3 RGD recognition site peptide, both of which block T4 binding to integrin αVβ3 but are not agonists. Activation of MAPK by T4 was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. The thyroid hormone 3,5,3′-triiodo-l-thyronine (T3) and T4 were equipotent stimulators of PCNA accumulation in C6, F98, and GL261 cells, but physiologic concentrations of T3 are 50-fold lower than those of T4. In conclusion, our studies suggest that glioblastoma cells are thyroid hormone dependent and provide a molecular basis for recent clinical observations that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients. The present experiments infer a novel cell membrane receptor-mediated basis for the growth-promoting activity of thyroid hormone in such tumors and suggest new therapeutic approaches to the treatment of patients with glioblastoma. (Cancer Res 2006; 66(14): 7270-5)
Extracellular Matrix–Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-β1
Authors: Ottaviano Adam J. , Sun Limin , Ananthanarayanan Vijayalakshmi , Munshi Hidayatullah G. 
Published: July 2006

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with an intense fibrotic reaction around the tumor known as desmoplastic reaction. This tissue is composed of interstitial matrix, predominantly type I collagen, together with proliferating fibroblastic cells. Despite the recognized importance of tumor-stromal interactions, very little is known about the interactions among pancreatic cells, myofibroblasts, and the interstitial matrix. The current study was undertaken to test the hypothesis that the desmoplastic reaction alters PDAC gene expression and cellular behavior. Evaluation of human pancreatic specimens showed increased fibrosis and enhanced membrane type 1-matrix metalloproteinase (MT1-MMP) expression in tumor specimens compared with normal pancreas. Using an in vitro model of tumor cell-stromal interactions, type I collagen and the extracellular matrix deposited by pancreatic fibroblasts and PDAC cells regulated motility of human papillomavirus–immortalized human pancreatic ductal epithelial (HPDE) cells. These “stromal” matrices also regulated MT1-MMP expression by HPDE cells, without affecting the expression of tissue inhibitor of metalloproteinase 2. Treatment with transforming growth factor-β1 (TGF-β1) type I receptor kinase inhibitors and function-blocking anti-TGF-β1 antibody abrogated matrix-mediated MT1-MMP induction. TGF-β1 also promoted MT1-MMP–dependent migration by HPDE cells. Moreover, compared with normal tissue, there was increased TGF-β1 signaling in grade 3 tumor specimens as shown by increased phospho-Smad2 staining. These data show that the crosstalk between cancer cells and stromal elements mediated by TGF-β1 influences cell surface– and pericellular matrix–degrading potential in vitro and may contribute to pancreatic cancer progression in vivo. (Cancer Res 2006; 66(14): 7032-40)
Absence of the Full-Length Breast Cancer–Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members
Authors: Shukla Vivek , Coumoul Xavier , Cao Liu , Wang Rui-Hong , Xiao Cuiying , Xu Xiaoling , Andò Sebastiano , Yakar Shoshana , LeRoith Derek , Deng Chuxia 
Published: July 2006

AbstractThe breast cancer–associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Δ11/Δ11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging. (Cancer Res 2006; 66(14): 7151-7)
Chemoprevention of Familial Adenomatous Polyposis by Low Doses of Atorvastatin and Celecoxib Given Individually and in Combination to APCMin Mice
Authors: Swamy Malisetty V. , Patlolla Jagan M.R. , Steele Vernon E. , Kopelovich Levy , Reddy Bandaru S. , Rao Chinthalapally V. 
Published: July 2006

Abstract
Preclinical and clinical studies have established evidence that cyclooxygenase-2 (COX-2) inhibitors and statins [hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors] inhibit colon carcinogenesis. Chronic use of high doses of COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of atorvastatin (Lipitor) and celecoxib individually or in combination in an animal model of familial adenomatous polyposis. Six-week-old male C57BL/6J-APCmin/+ mice were either fed diets containing 0 or 100 ppm atorvastatin or 300 ppm celecoxib, or a combination of both for ∼80 days. Mice were sacrificed, and their intestines were scored for tumors. Normal-seeming mucosa and intestinal tumors were harvested and assayed for apoptosis (terminal deoxynucleotidyl transferase–mediated nick-end labeling) and HMGR and COX-2 protein expression and activity. We observed that 100 ppm atorvastatin significantly (P &lt; 0.002) suppressed intestinal polyp formation. As anticipated, 300 ppm celecoxib decreased the rate of formation of intestinal polyps by ∼70% (P &lt; 0.0001). Importantly, the combination of 100 ppm atorvastatin and 300 ppm celecoxib in the diet suppressed the colon polyps completely and small intestinal polyps by &gt;86% (P &lt; 0.0001) compared with the control group. The inhibition of tumor formation by the atorvastatin and celecoxib combination was significant (P &lt; 0.005) when compared with tumor inhibition by celecoxib alone. In addition, increased rates of apoptosis in intestinal tumors (P &lt; 0.01-0.0001) were observed in animals fed with atorvastatin and celecoxib and more so with the combinations. Tumors of animals fed atorvastatin showed a significant decrease in HMGR-R activity. Similarly, tumors of mice exposed to celecoxib showed significantly lower levels of COX-2 activity. These observations show that atorvastatin inhibits intestinal tumorigenesis and that, importantly, when given together with low doses of celecoxib, it significantly increases the chemopreventive efficacy in an APCmin mice. (Cancer Res 2006; 66(14): 7370-7)
Disruption of EphA2 Receptor Tyrosine Kinase Leads to Increased Susceptibility to Carcinogenesis in Mouse Skin
Authors: Guo Hong , Miao Hui , Gerber Lizabeth , Singh Jarnail , Denning Mitchell F. , Gilliam Anita C. , Wang Bingcheng 
Published: July 2006

Abstract
EphA2 receptor tyrosine kinase is frequently overexpressed in different human cancers, suggesting that it may promote tumor development and progression. However, evidence also exists that EphA2 may possess antitumorigenic properties, raising a critical question on the role of EphA2 kinase in tumorigenesis in vivo. We report here that deletion of EphA2 in mouse led to markedly enhanced susceptibility to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. EphA2-null mice developed skin tumors with an increased frequency and shortened latency. Moreover, tumors in homozygous knockout mice grew faster and were twice as likely to show invasive malignant progression. Haploinsufficiency of EphA2 caused an intermediate phenotype in tumor development but had little effects on invasive progression. EphA2 and ephrin-A1 exhibited compartmentalized expression pattern in mouse skin that localized EphA2/ephrin-A1 interactions to the basal layer of epidermis, which was disrupted in tumors. Loss of EphA2 increased tumor cell proliferation, whereas apoptosis was not affected. In vitro, treatment of primary keratinocytes from wild-type mice with ephrin-A1 suppressed cell proliferation and inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) activities. Both effects were abolished in EphA2-null keratinocytes, suggesting that loss of ERK inhibition by EphA2 may be one of the contributing mechanisms for increased tumor susceptibility. Interestingly, despite its tumor suppressive function, EphA2 was overexpressed in skin tumors compared with surrounding normal skin in wild-type mice, similar to the observations in human cancers. EphA2 overexpression may represent a compensatory feedback mechanism during tumorigenesis. Together, these results show that EphA2 is a novel tumor suppressor gene in mammalian skin. (Cancer Res 2006; 66(14): 7050-8)
Survival Response to B-Cell Receptor Ligation Is Restricted to Progressive Chronic Lymphocytic Leukemia Cells Irrespective of Zap70 Expression
Authors: Deglesne Pierre-Antoine , Chevallier Nathalie , Letestu Rémi , Baran-Marszak Fanny , Beitar Taoufik , Salanoubat Célia , Sanhes Laurence , Nataf Joelle , Roger Claudine , Varin-Blank Nadine , Ajchenbaum-Cymbalista Florence 
Published: July 2006

Abstract
Despite very similar gene expression profiles, the clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is heterogeneous. Immunoglobulin VH (IgVH) mutational status and expression of B-cell receptor (BCR) signaling mediators have been associated with disease progression. However, the consequences of BCR engagement on cell survival and evolution of the disease remain unclear. We show here that B-CLL cell survival is dependent on the threshold of BCR stimulation induced by immobilized antibody, in contrast to soluble anti-μ F(ab)′2 antibody, which leads to apoptosis. Measurement of metabolic activity and apoptotic response discriminated two subgroups. “Nonresponders” showed low metabolic activity and unmodified apoptotic response upon BCR stimulation. In contrast, “responders” exhibited increased metabolic activity and inhibition of spontaneous apoptosis. This survival advantage was associated to a BCR-dependent activation profile leading to induction of cyclin D2/cyclin-dependent kinase 4 (cdk4) expression and G1 cell cycle progression. The ability to respond to BCR ligation correlated with an unfavorable clinical course and allowed to define an additional group of patients among IgVH-mutated cases exhibiting a risk of progression. Remarkably, we show that Zap70 expression was neither mandatory nor sufficient to generate downstream survival signals and cyclin D2/cdk4 up-regulation. In conclusion, BCR engagement has a significant effect on B-CLL cell survival, activation, and G1 progression. Furthermore, our results provide new insights in the physiopathology of progressive IgVH-mutated cases. (Cancer Res 2006; 66(14): 7158-66)
Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice
Authors: Oster Henrik , Leitges Michael 
Published: July 2006

Abstract
Members of the protein kinase C (PKC) family of serine/threonine kinases play key regulatory roles in numerous cellular processes, including differentiation and proliferation. Of the 11 mammalian PKC isoforms known, several have been implicated in tumor development and progression. However, in most cases, isotype specificity is poorly defined, and even contrary functions for a single PKC have been reported mostly because appropriate molecular and genetic tools were missing to specifically assess the contribution of single PKC isoforms in vivo. In this report, we therefore used PKC genetic targeting to study the role of PKCα and PKCζ in colorectal cancer. Both isoforms were found to be strongly down-regulated in intestinal tumors of ApcMin/+ mice. A deletion of PKCζ did not affect tumorigenesis in this animal model. In contrast, PKCα-deficient ApcMin/+ mice developed more aggressive tumors and died significantly earlier than their PKCα-proficient littermates. Even without an additional Apc mutation, PKCα knockout mice showed an elevated tendency to develop spontaneous intestinal tumors. Transcriptional profiling revealed a role for this kinase in regulating epidermal growth factor receptor (EGFR) signaling and proposed a synergistic mechanism for EGFR/activator protein and WNT/APC pathways in mediating intestinal tumor development. (Cancer Res 2006; 66(14): 6955-63)