bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Molecular Classification of Papillary Renal Cell Carcinoma
Authors: Yang Ximing J. , Tan Min-Han , Kim Hyung L. , Ditlev Jonathon A. , Betten Mark W. , Png Carolina E. , Kort Eric J. , Futami Kunihiko , Furge Kyle A. , Takahashi Masayuki , Kanayama Hiro-omi , Tan Puay Hoon , Teh Bin Sing , Luan Chunyan , Wang Kim , Pins Michael , Tretiakova Maria , Anema John , Kahnoski Richard , Nicol Theresa , Stadler Walter , Vogelzang Nicholas G. , Amato Robert , Seligson David , Figlin Robert , Belldegrun Arie , Rogers Craig G. , Teh Bin Tean
Published: March 2023

Abstract
Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIα in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.
Data from Human Aromatase: Gene Resequencing and Functional Genomics
Authors: Ma Cynthia X. , Adjei Araba A. , Salavaggione Oreste E. , Coronel Josefa , Pelleymounter Linda , Wang Liewei , Eckloff Bruce W. , Schaid Daniel , Wieben Eric D. , Adjei Alex A. , Weinshilboum Richard M.
Published: March 2023

Abstract
Aromatase [cytochrome P450 19 (CYP19)] is a critical enzyme for estrogen biosynthesis, and aromatase inhibitors are of increasing importance in the treatment of breast cancer. We set out to identify and characterize genetic polymorphisms in the aromatase gene, CYP19, as a step toward pharmacogenomic studies of aromatase inhibitors. Specifically, we “resequenced” all coding exons, all upstream untranslated exons plus their presumed core promoter regions, all exon-intron splice junctions, and a portion of the 3′-untranslated region of CYP19 using 240 DNA samples from four ethnic groups. Eighty-eight polymorphisms were identified, resulting in 44 haplotypes. Functional genomic studies were done with the four nonsynonymous coding single nucleotide polymorphisms (cSNP) that we observed, two of which were novel. Those cSNPs altered the following amino acids: Trp39Arg, Thr201Met, Arg264Cys, and Met364Thr. The Cys264, Thr364, and double variant Arg39Cys264 allozymes showed significant decreases in levels of activity and immunoreactive protein when compared with the wild-type (WT) enzyme after transient expression in COS-1 cells. A slight decrease in protein level was also observed for the Arg39 allozyme, whereas Met201 displayed no significant changes in either activity or protein level when compared with the WT enzyme. There was also a 4-fold increase in apparent Km value for Thr364 with androstenedione as substrate. Of the recombinant allozymes, only the double mutant (Arg39Cys264) displayed a significant change from the WT enzyme in inhibitor constant for the aromatase inhibitors exemestane and letrozole. These observations indicate that genetic variation in CYP19 might contribute to variation in the pathophysiology of estrogen-dependent disease.
Data from Inhibition of DNA Methyltransferase Activity Prevents Tumorigenesis in a Mouse Model of Prostate Cancer
Authors: McCabe Michael T. , Low Jonathan A. , Daignault Stephanie , Imperiale Michael J. , Wojno Kirk J. , Day Mark L.
Published: March 2023

Abstract
Transcriptional silencing of tumor suppressor genes by DNA methylation plays an important role in tumorigenesis. These aberrant epigenetic modifications may be mediated in part by elevated DNA methyltransferase levels. DNA methyltransferase 1 (DNMT1), in particular, is overexpressed in many tumor types. Recently, we showed that Dnmt1 is transcriptionally regulated by E2F transcription factors and that retinoblastoma protein (pRb) inactivation induces Dnmt1. Based on these observations, we investigated regulation of Dnmt1 by polyomavirus oncogenes, which potently inhibit the pRb pocket protein family. Infection of primary human prostate epithelial cells with BK polyomavirus dramatically induced Dnmt1 transcription following large T antigen (TAg) translation and E2F activation. For in vivo study of Dnmt1 regulation, we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which expresses the SV40 polyomavirus early region, including TAg, under control of a prostate-specific promoter. Analysis of TRAMP prostate lesions revealed greatly elevated Dnmt1 mRNA and protein levels beginning in prostatic intraepithelial neoplasia and continuing through advanced prostate cancer and metastasis. Interestingly, when TRAMP mice were treated in a chemopreventive manner with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza), 0 of 14 mice developed prostate cancer at 24 weeks of age, whereas 7 of 13 (54%) control-treated mice developed poorly differentiated prostate cancer. Treatment with 5-aza also prevented the development of lymph node metastases and dramatically extended survival compared with control-treated mice. Taken together, these data suggest that Dnmt1 is rapidly activated by pRb pathway inactivation, and that DNA methyltransferase activity is required for malignant transformation and tumorigenesis. (Cancer Res 2006; 66(1): 385-92)
Data from Cloning and Characterization of a p53 and DNA Damage Down-regulated Gene PIQ that Codes for a Novel Calmodulin-Binding IQ Motif Protein and Is Up-regulated in Gastrointestinal Cancers
Authors: Luo Xiuquan , He Qin , Huang Ying , Sheikh M. Saeed
Published: March 2023

Abstract
We have identified a p53 and DNA damage–regulated gene that encodes a novel IQ motif protein, which we have named p53 and DNA damage–regulated IQ motif protein (PIQ). PIQ has two isoforms, long (PIQ-L) and short (PIQ-S), and both bind to calmodulin in the presence and absence of calcium. PIQ expression is down-regulated by p53 and DNA damage–inducing agents, whereas PIQ itself represses the expression of p53 up-regulated modulator of apoptosis that is a key mediator of p53-induced apoptosis. Thus, PIQ is a novel protein that may function to bridge a crosstalk between p53 and calmodulin-regulated cellular processes. We further show that PIQ expression is up-regulated in a number of primary colorectal and gastric tumors when compared with matching normal tissues, suggesting that PIQ may be involved in tumorigenesis and could serve as a valuable diagnostic/prognostic marker for gastrointestinal tumors.
Data from Mechanism of Increased Coxsackie and Adenovirus Receptor Gene Expression and Adenovirus Uptake by Phytoestrogen and Histone Deacetylase Inhibitor in Human Bladder Cancer Cells and the Potential Clinical Application
Authors: Pong Rey-Chen , Roark Ryan , Ou Jiun-Yih , Fan Jianhai , Stanfield Jennifer , Frenkel Eugene , Sagalowsky Arthur , Hsieh Jer-Tsong
Published: March 2023

Abstract
Coxsackie and adenovirus receptor (CAR) is known as a principal receptor for adenovirus commonly used as a gene delivery vector. Down-regulation of CAR is often detected in several cancer types. Epigenetic modifiers such as histone deacetylase inhibitor FK228 (depsipeptide) have been shown to increase CAR expression as well as the uptake of adenovirus in bladder cancer in vivo and in vitro, indicating that altered transcriptional regulation of CAR is the key mechanism responsible for the decreased CAR levels in this cancer. In this study, we screened agents that could induce CAR expression in bladder cancer cells. Fifty-eight drugs with various chemical properties were tested. Ipriflavone and plant isoflavones were found to exhibit the ability to induce CAR gene expression in combination with FK228. Genistein, the natural isoflavone found in soybean, when combined with FK228, exerts a synergistic effect on CAR gene and protein expression in bladder cancer cells. Chromatin immunoprecipitation results showed an increased histone acetylation in the CAR promoter gene, which is due to the suppression of histone deacetylase activity by both agents. Also, our data indicated that combination treatment is a potent chemotherapeutic regimen for bladder cancer cells and the subsequent administration of recombinant adenovirus could further eliminate the remaining cells. Taken together, our results provide a strong rationale for combining chemotherapeutic and gene therapeutic agents to enhance the therapeutic efficacy in bladder cancer. (Cancer Res 2006; 66(17): 8822-8)
Data from Identification of Src-Specific Phosphorylation Site on Focal Adhesion Kinase: Dissection of the Role of Src SH2 and Catalytic Functions and Their Consequences for Tumor Cell Behavior
Authors: Brunton Valerie G. , Avizienyte Egle , Fincham Valerie J. , Serrels Bryan , Metcalf Chester A. , Sawyer Tomi K. , Frame Margaret C.
Published: March 2023

Abstract
Src tyrosine kinase expression and activity are elevated during colon cancer progression. How this contributes to the malignant phenotype is not fully understood. We show that in KM12C colon carcinoma cells, expression of kinase-deficient Src proteins (SrcMF and Src251) does not alter cell growth. Src kinase activity is required for turnover of cell-matrix adhesions and, in particular, the Src-dependent phosphorylation of focal adhesion kinase (FAK) is required for their disassembly. Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr407, Tyr576, Tyr577, and Tyr861, which are considered to be Src kinase substrates. This Src kinase–independent phosphorylation of FAK required an intact Src SH2 domain that mediates association of Src and FAK at peripheral adhesions. Use of a novel highly potent and selective Src kinase inhibitor AP23464 combined with experiments in Src/Fyn/Yes–deficient fibroblasts showed that increased phosphorylation of FAK in cells expressing SrcMF did not require Src-like kinases. However, specific phosphorylation on Tyr925 of FAK was not evident in SrcMF- or Src251-expressing cells, and lack of Src kinase–dependent phosphorylation on this site was associated with impaired adhesion turnover. Our data show that Src kinase activity is required for adhesion turnover associated with cell migration in cancer cells and that, in addition to the catalytic activity, Src also acts as an adaptor to recruit other kinases that can phosphorylate key substrates including FAK. These studies have implications for tumor progression with respect to the use of Src kinase inhibitors.
Data from Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor β Signaling in Human Prostate Cancer Cells
Authors: Zhu Beibei , Fukada Kei , Zhu Haining , Kyprianou Natasha
Published: March 2023

Abstract
A proteomic analysis was pursued to identify new signaling effectors of transforming growth factor β1 (TGF-β1) that serve as potential intracellular effectors of its apoptotic action in human prostate cancer cells. The androgen-sensitive and TGF-β-responsive human prostate cancer cells, LNCaP TβRII, were used as in vitro model. In response to TGF-β, significant posttranslational changes in two proteins temporally preceded apoptotic cell death. TGF-β mediated the nuclear export of prohibitin, a protein involved in androgen-regulated prostate growth, to the cytosol in the LNCaP TβRII cells. Cofilin, a protein involved in actin depolymerization, cell motility, and apoptosis, was found to undergo mitochondrial translocation in response to TGF-β before cytochrome c release. Loss-of-function approaches (small interfering RNA) to silence prohibitin expression revealed a modest decrease in the apoptotic response to TGF-β and a significant suppression in TGF-β-induced cell migration. Silencing Smad4 showed that the cellular localization changes associated with prohibitin and cofilin action in response to TGF-β are independent of Smad4 intracellular signaling. (Cancer Res 2006; 66(17): 8640-7)
Data from CD1d-Restricted T Cells License B Cells to Generate Long-Lasting Cytotoxic Antitumor Immunity In vivo
Authors: Chung Yeonseok , Kim Byung-Seok , Kim Yeon-Jeong , Ko Hyun-Jeong , Ko Sung-Youl , Kim Dong-Hyeon , Kang Chang-Yuil
Published: March 2023

Abstract
Although resting B cells are known for being poorly immunogenic and for inducing T-cell tolerance, we have here attempted to test whether their immunogenicity could be enhanced by CD1d-restricted invariant T cells (iNKT) to a point where they could be used in cellular vaccines. We found that the addition of the iNKT ligand α-galactosylceramide (αGalCer) to peptide-loaded B cells overcame peptide-specific T-cell unresponsiveness and allowed for the generation of peptide-specific memory CTL immunity. This CTL was induced independently of CD4 T and natural killer cells but required iNKT and CD8 T cells. B cells directly primed CTL, and the αGalCer and the peptide must be presented on the same cell. Importantly, our B-cell–based vaccine is comparable in efficiency with dendritic cell–based vaccines, inducing similar CTL responses as well as providing an effective regimen for preventing and suppressing s.c. and metastatic tumors. Therefore, with the help of iNKT, peptide-pulsed B cells can establish long-lasting antitumor immunity and so show promise as the basis for an alternative cell-based vaccine. (Cancer Res 2006; 66(13): 6843-50)
Data from Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas
Authors: Bredel Markus , Bredel Claudia , Juric Dejan , Harsh Griffith R. , Vogel Hannes , Recht Lawrence D. , Sikic Branimir I.
Published: March 2023

Abstract
Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.
Data from Insertion of c-Myc into Igh Induces B-Cell and Plasma-Cell Neoplasms in Mice
Authors: Park Sung Sup , Kim Joong Su , Tessarollo Lino , Owens James D. , Peng Liangping , Han Seong Su , Tae Chung Seung , Torrey Ted A. , Cheung Wan C. , Polakiewicz Roberto D. , McNeil Nicole , Ried Thomas , Mushinski J. Frederic , Morse Herbert C. , Janz Siegfried
Published: March 2023

Abstract
We used gene targeting in mice to insert a His6-tagged mouse c-Myc cDNA, MycHis, head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5′ of the intronic enhancer, Eμ. The insertion of MycHis mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, MycHis transgenic mice developed B-cell and plasma neoplasms, such as IgM+ lymphoblastic B-cell lymphomas, Bcl-6+ diffuse large B-cell lymphomas, and CD138+ plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed MycHis, and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of MycHis, suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19Arf-Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that MycHis insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation.
Data from Interleukin-17 Receptor-Like Gene Is a Novel Antiapoptotic Gene Highly Expressed in Androgen-Independent Prostate Cancer
Authors: You Zongbing , Shi Xu-Bao , DuRaine Grayson , Haudenschild Dominik , Tepper Clifford G. , Hao Lo Su , Gandour-Edwards Regina , de Vere White Ralph W. , Reddi A. Hari
Published: March 2023

Abstract
We have recently identified a new gene, interleukin-17 receptor-like (IL-17RL), which is expressed in normal prostate and prostate cancer. This investigation is focused on the role of IL-17RL in prostate cancer. We found that IL-17RL was expressed at significantly higher levels in several androgen-independent prostate cancer cell lines (PC3, DU145, cds1, cds2, and cds3) and tumors compared with the androgen-dependent cell lines (LNCaP and MLC-SV40) and tumors. In an in vivo model of human prostate tumor growth in nude mice (CWR22 xenograft model), IL-17RL expression in tumors was induced by androgen deprivation. The relapsed androgen-independent tumors expressed higher levels of IL-17RL compared with the androgen-dependent tumors. Overexpression of IL-17RL in tumor necrosis factor α (TNFα)–sensitive LNCaP cells inhibited TNFα-induced apoptosis by blocking activation of caspase-3 downstream to caspase-2 and caspase-8. Reciprocally, knocking down IL-17RL expression by small interfering RNA induced apoptosis in all the prostate cancer cell lines studied. Taken together, these results show that IL-17RL is a novel antiapoptotic gene, which may confer partially the property of androgen-independent growth of prostate cancer by promoting cell survival. Thus, IL-17RL is a potential therapeutic target in the treatment of prostate cancer. (Cancer Res 2006; 66(1): 175-83)
Data from Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase
Authors: Cohen Ezra Eddy Wyssam , Lingen Mark W. , Zhu Bangmin , Zhu Hongyan , Straza Michael Wayne , Pierce Carolyn , Martin Leslie E. , Rosner Marsha Rich
Published: March 2023

Abstract
Protein kinase C (PKC) ζ has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCζ is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCζ expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCζ expression from normal to malignant tissue. PKCζ activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCζ using either kinase-dead PKCζ mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCζ inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCζ is associated with SCCHN progression, (b) PKCζ mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCζ mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCζ inhibitors function additively with other inhibitors that target similar or complementary signaling pathways. (Cancer Res 2006; 66(12): 6296-303)
Data from Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients
Authors: Hampel Heather , Frankel Wendy , Panescu Jenny , Lockman Janet , Sotamaa Kaisa , Fix Daniel , Comeras Ilene , La Jeunesse Jennifer , Nakagawa Hidewaki , Westman Judith A. , Prior Thomas W. , Clendenning Mark , Penzone Pamela , Lombardi Janet , Dunn Patti , Cohn David E. , Copeland Larry , Eaton Lynne , Fowler Jeffrey , Lewandowski George , Vaccarello Luis , Bell Jeffrey , Reid Gary , de la Chapelle Albert
Published: March 2023

Abstract
Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation–positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable. (Cancer Res 2006; 66(15): 7810-7)
Data from Insertion of Myc into Igh Accelerates Peritoneal Plasmacytomas in Mice
Authors: Park Sung Sup , Shaffer Arthur L. , Kim Joong Su , duBois Wendy , Potter Michael , Staudt Louis M. , Janz Siegfried
Published: March 2023

Abstract
Gene-targeted mice that contain a His6-tagged mouse c-Myc cDNA, MycHis, inserted head to head into different sites of the mouse immunoglobulin heavy-chain locus, Igh, mimic the chromosomal T(12;15)(Igh-Myc) translocation that results in the activation of Myc in the great majority of mouse plasmacytomas. Mice carrying MycHis just 5′ of the intronic heavy-chain enhancer Eμ (strain iMycEμ) provide a specific model of the type of T(12;15) found in a subset (∼20%) of plasmacytomas that develop “spontaneously” in the gut-associated lymphoid tissue (GALT) of interleukin-6 transgenic BALB/c (C) mice. Here we show that the transfer of the iMycEμ transgene from a mixed genetic background of segregating C57BL/6 × 129/SvJ alleles to the background of C increased the incidence of GALT plasmacytomas by a factor of 2.5 in first-generation backcross mice (C.iMycEμ N1). Third-generation backcross mice (C.iMycEμ N3, ∼94% C alleles) were hypersusceptible to inflammation-induced peritoneal plasmacytomas (tumor incidence, 100%; mean tumor onset, 86 ± 28 days) compared with inbred C mice (tumor incidence, 5% on day 150 after tumor induction). Peritoneal plasmacytomas of C.iMycEμ N3 mice overexpressed MycHis, produced monoclonal immunoglobulin, and exhibited a unique plasma cell signature upon gene expression profiling on mouse Lymphochip cDNA microarrays. These findings indicated that the iMycEμ transgene accelerates plasmacytoma development by collaborating with tumor susceptibility alleles of strain C and circumventing the requirement for tumor precursors to acquire deregulated Myc by chromosomal translocation.
Data from Potent Antiandrogen and Androgen Receptor Activities of an Angelica gigas–Containing Herbal Formulation: Identification of Decursin as a Novel and Active Compound with Implications for Prevention and Treatment of Prostate Cancer
Authors: Jiang Cheng , Lee Hyo-Jeong , Li Guang-xun , Guo Junming , Malewicz Barbara , Zhao Yan , Lee Eun-Ok , Lee Hyo-Jung , Lee Jae-Ho , Kim Min-Seok , Kim Sung-Hoon , Lu Junxuan
Published: March 2023

Abstract
Androgen and androgen receptor (AR)–mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, ∼7 μg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of ∼0.4 μg/mL (1.3 μmol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases. (Cancer Res 2006; 66(1): 453-63)
Data from Dissociation of Angiogenesis and Tumorigenesis in Follistatin- and Activin-Expressing Tumors
Authors: Krneta Jelena , Kroll Jens , Alves Frauke , Prahst Claudia , Sananbenesi Farahnaz , Dullin Christian , Kimmina Sarah , Phillips David J. , Augustin Hellmut G.
Published: March 2023

Abstract
The transforming growth factor-β superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2–induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained. (Cancer Res 2006; 66(11): 5686-95)
Data from Divergent Routes to Oral Cancer
Authors: Hunter Keith D. , Thurlow Johanna K. , Fleming Janis , Drake Paul J.H. , Vass J. Keith , Kalna Gabriela , Higham Des J. , Herzyk Pawel , MacDonald D. Gordon , Parkinson E. Ken , Harrison Paul R.
Published: March 2023

Abstract
Most head and neck squamous cell carcinoma (HNSCC) patients present with late-stage cancers, which are difficult to treat. Therefore, early diagnosis of high-risk premalignant lesions and incipient cancers is important. HNSCC is currently perceived as a single progression mechanism, resulting in immortal invasive cancers. However, we have found that ∼40% of primary oral SCCs are mortal in culture, and these have a better prognosis. About 60% of oral premalignancies (dysplasias) are also mortal. The mortal and immortal tumors are generated in vivo as judged by p53 mutations and loss of p16INK4A expression being found only in the original tumors from which the immortal cultures were derived. To investigate the relationships of dysplasias to SCCs, we did microarray analysis of primary cultures of 4 normal oral mucosa biopsies, 19 dysplasias, and 16 SCCs. Spectral clustering using the singular value decomposition and other bioinformatic techniques showed that development of mortal and immortal SCCs involves distinct transcriptional changes. Both SCC classes share most of the transcriptional changes found in their respective dysplasias but have additional changes. Moreover, high-risk dysplasias that subsequently progress to SCCs more closely resemble SCCs than nonprogressing dysplasias. This indicates for the first time that there are divergent mortal and immortal pathways for oral SCC development via intermediate dysplasias. We believe that this new information may lead to new ways of classifying HNSCC in relation to prognosis. (Cancer Res 2006; 66(15): 7405-13)
Data from Aptamer:Toxin Conjugates that Specifically Target Prostate Tumor Cells
Authors: Chu Ted C. , Marks John W. , Lavery Laura A. , Faulkner Sarah , Rosenblum Michael G. , Ellington Andrew D. , Levy Matthew
Published: March 2023

Abstract
We have used RNA aptamer:gelonin conjugates to target and specifically destroy cells overexpressing the known cancer biomarker prostate-specific membrane antigen (PSMA). Aptamer:toxin conjugates have an IC50 of 27 nmol/L and display an increased potency of at least 600-fold relative to cells that do not express PSMA. The aptamer not only promotes uptake into target cells but also decreases the toxicity of gelonin in non-target cells. These results validate the notion that “escort aptamers” may be useful for the treatment of specific tumors expressing unique antigen targets.(Cancer Res 2006; 66(12): 5989-92)
Data from Spontaneous Fusion with, and Transformation of Mouse Stroma by, Malignant Human Breast Cancer Epithelium
Authors: Jacobsen Britta M. , Harrell J. Chuck , Jedlicka Paul , Borges Virginia F. , Varella-Garcia Marileila , Horwitz Kathryn B.
Published: March 2023

Abstract
Adenocarcinoma cells from the pleural effusion of a patient with breast cancer were injected into the mammary glands of nude mice and grown into solid tumors. A cell line derived from these tumors expressed α-smooth muscle actin but not human cytokeratin 7, indicating “activated” stroma of mouse origin. Cells in mitosis exhibited mainly polyploid mouse karyotypes, but 30% had mixed mouse and human chromosomes, among which 8% carried mouse/human translocations. Nuclei of interphase cells were 64% hybrid. Hybrid mouse/human nuclei were also detected in the primary xenograft. Thus, synkaryons formed in the solid tumor by spontaneous fusion between the malignant human epithelium and the surrounding normal host mouse stroma. The transformed stroma-derived cells are tumorigenic with histopathologic features of malignancy, suggesting a new mechanism for tumor progression. (Cancer Res 2006; 66(16): 8274-9)
Data from Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma
Authors: Ogushi Tetsuo , Takahashi Satoru , Takeuchi Takumi , Urano Tomohiko , Horie-Inoue Kuniko , Kumagai Jinpei , Kitamura Tadaichi , Ouchi Yasuyoshi , Muramatsu Masami , Inoue Satoshi
Published: March 2023

Abstract
The estrogen receptor–binding fragment–associated antigen 9 (EBAG9) has been identified as a primary estrogen-responsive gene in human breast cancer MCF7 cells. A high expression of EBAG9 has been observed in invasive breast cancer and advanced prostate cancer, suggesting a tumor-promoting role of the protein in malignancies. Here we show that intratumoral (i.t.) administration of small interfering RNA against EBAG9 exerted overt regression of tumors following s.c. implantation of murine renal cell carcinoma (RCC) Renca cells. Overexpression of EBAG9 did not promote the proliferation of culture Renca cells; however, the inoculated Renca cells harboring EBAG9 (Renca-EBAG9) in BALB/c mice grew faster and developed larger tumors compared with Renca cells expressing vector alone (Renca-vector). After renal subcapsular implantation, Renca-EBAG9 tumors significantly enlarged compared with Renca-vector tumors in BALB/c mice, whereas both Renca-EBAG9 and Renca-vector tumors were developed with similar volumes in BALB/c nude mice. No apparent difference was observed in specific cytotoxic T-cell responses against Renca-EBAG9 and Renca-vector cells; nonetheless, the number of infiltrating CD8+ T lymphocytes was decreased in Renca-EBAG9 subcapsular tumors. Furthermore, immunohistochemical study of EBAG9 in 78 human RCC specimens showed that intense and diffuse cytoplasmic immunostaining was observed in 87% of the cases and positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients. Multivariate analysis revealed that high EBAG9 expression was an independent prognostic predictor for disease-specific survival (P = 0.0485). Our results suggest that EBAG9 is a crucial regulator of tumor progression and a potential prognostic marker for RCC.
Data from β1 Integrin Inhibitory Antibody Induces Apoptosis of Breast Cancer Cells, Inhibits Growth, and Distinguishes Malignant from Normal Phenotype in Three Dimensional Cultures and In vivo
Authors: Park Catherine C. , Zhang Hui , Pallavicini Maria , Gray Joe W. , Baehner Frederick , Park Chong J. , Bissell Mina J.
Published: March 2023

Abstract
Current therapeutic approaches to cancer are designed to target molecules that contribute to malignant behavior but leave normal tissues intact. β1 integrin is a candidate target well known for mediating cell-extracellular matrix (ECM) interactions that influence diverse cellular functions; its aberrant expression has been implicated in breast cancer progression and resistance to cytotoxic therapy. The addition of β1 integrin inhibitory agents to breast cancer cells at a single-cell stage in a laminin-rich ECM (three-dimensional lrECM) culture was shown to down-modulate β1 integrin signaling, resulting in malignant reversion. To investigate β1 integrin as a therapeutic target, we modified the three-dimensional lrECM protocol to approximate the clinical situation: before treatment, we allowed nonmalignant cells to form organized acinar structures and malignant cells to form tumor-like colonies. We then tested the ability of β1 integrin inhibitory antibody, AIIB2, to inhibit tumor cell growth in several breast cancer cell lines (T4-2, MDA-MB-231, BT474, SKBR3, and MCF-7) and one nonmalignant cell line (S-1). We show that β1 integrin inhibition resulted in a significant loss of cancer cells, associated with a decrease in proliferation and increase in apoptosis, and a global change in the composition of residual colonies. In contrast, nonmalignant cells that formed tissue-like structures remained resistant. Moreover, these cancer cell–specific antiproliferative and proapoptotic effects were confirmed in vivo with no discernible toxicity to animals. Our findings indicate that β1 integrin is a promising therapeutic target, and that the three-dimensional lrECM culture assay can be used to effectively distinguish malignant and normal tissue response to therapy. (Cancer Res 2006; 66(3): 1526-35)
Data from Adiponectin Modulates the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway and Attenuates Mammary Tumorigenesis of MDA-MB-231 Cells in Nude Mice
Authors: Wang Yu , Lam Janice B. , Lam Karen S.L. , Liu Jing , Lam Michael C. , Hoo Ruby L.C. , Wu Donghai , Cooper Garth J.S. , Xu Aimin
Published: March 2023

Abstract
Adiponectin is an adipokine that has pleiotropic beneficial roles in systemic insulin resistance and inflammation. Several recent clinical studies suggest that low serum levels of adiponectin are associated with increased risks of breast cancer. Here, we investigated the direct effects of adiponectin on breast cancer development in vitro and in vivo. Our results showed that adiponectin significantly attenuated the proliferations of two typical human breast cancer cells, MDA-MB-231 and T47D, in a cell type–specific manner. Further analysis revealed that adiponectin could induce apoptosis and arrest the cell cycle progression at G0-G1 phase in MDA-MB-231 cells. Prolonged treatment with adiponectin in this cell line blocked serum-induced phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), suppressed intracellular accumulation of β-catenin and its nuclear activities, and consequently reduced expression of cyclin D1. Adiponectin-mediated suppression of cyclin D1 expression and attenuation of cell proliferation was abrogated by the GSK-3β inhibitor lithium chloride. These results suggest that the inhibitory role of adiponectin on MDA-MB-231 cell growth might be attributed to its suppressive effects on the GSK-3β/β-catenin signaling pathway. Furthermore, our in vivo study showed that both supplementation of recombinant adiponectin and adenovirus-mediated overexpression of this adipokine substantially reduced the mammary tumorigenesis of MDA-MB-231 cells in female nude mice. Taken together, these data support the role of adiponectin as a negative regulator of breast cancer development and also suggest that adiponectin might represent a novel therapeutic target for this disease. (Cancer Res 2006; 66(23): 11462-70)
Data from Preferential Expression of Very Late Antigen-4 on Type 1 CTL Cells Plays a Critical Role in Trafficking into Central Nervous System Tumors
Authors: Sasaki Kotaro , Zhu Xinmei , Vasquez Cecilia , Nishimura Fumihiko , Dusak Jill E. , Huang Jian , Fujita Mitsugu , Wesa Amy , Potter Douglas M. , Walker Paul R. , Storkus Walter J. , Okada Hideho
Published: March 2023

Abstract
We have previously shown preferential tumor-homing and therapeutic efficacy of adoptively transferred type 1 CTL (Tc1) when compared with type 2 CTL (Tc2) in mice bearing intracranial ovalbumin-transfected melanoma (M05). Further characterizing the expression of a panel of homing receptors on Tc1 and Tc2 cells, we found that very late antigen (VLA)-4 (a heterodimer of CD49d and CD29), but none of other receptors evaluated, was expressed at significantly higher levels on Tc1 cells than on Tc2 cells. Although CD49d (α4 integrin) can form heterodimers with both β1 (CD29) and β7 integrins, α4β7 complexes were not expressed by either Tc1 or Tc2 cells, suggesting that CD49d is solely expressed in VLA-4 complexes. VLA-4 expression on Tc2 cells was down-regulated in an interleukin (IL)-4 dose-dependent manner but not by other type 2 cytokines, such as IL-10 and IL-13, suggesting that IL-4 uniquely down-regulates VLA-4 expression on these cells. In accordance with the differential expression of VLA-4 on Tc1 versus Tc2 cells, Tc1 cells alone were competent to adhere to plate-bound VCAM-1-Ig fusion protein. Finally, the efficient trafficking of Tc1 cells into intracranial M05 lesions in vivo was efficiently blocked by administration of monoclonal antibodies against CD49d or VCAM-1 or small interfering RNA–mediated silencing of CD49d on Tc1 cells. Collectively, these data support the critical role of VLA-4 in the effective intracranial tumor homing of adoptive-transferred, antigen-specific Tc1 cells and suggest that more effective vaccine and/or ex vivo T-cell activation regimens may be developed by promoting the generation of VLA-4+ antitumor Tc1 cells. [Cancer Res 2007;67(13):6451–8]
Data from Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells
Authors: Afshar Golnar , Jelluma Nannette , Yang Xiaodong , Basila Daniel , Arvold Nils D. , Karlsson Amelia , Yount Garret L. , Dansen Tobias B. , Koller Erich , Haas-Kogan Daphne A.
Published: March 2023

Abstract
Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation. (Cancer Res 2006; 66(8): 4223-32)
Data from Human Mucin 1 Oncoprotein Represses Transcription of the p53 Tumor Suppressor Gene
Authors: Wei Xiaolong , Xu Hai , Kufe Donald
Published: March 2023

Abstract
The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in human breast cancers and induces transformation. The MUC1 COOH-terminal subunit (MUC1-C) is targeted to the nucleus of transformed cells, where it interacts with p53 and regulates p53-mediated transcription. The present studies show that MUC1 represses activation of the p53 gene and that MUC1-C occupies the PE21 element in the p53 proximal promoter. Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21. The results also show that MUC1-C increases the recruitment of histone deacetylases 1/3, deacetylation of core histones, and repression of p53 transcription. These findings indicate that overexpression of MUC1, as found in human breast cancer cells, is of functional importance to repression of the p53 gene. [Cancer Res 2007;67(4):1853–8]
Data from Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer
Authors: Tsafrir Dafna , Bacolod Manny , Selvanayagam Zachariah , Tsafrir Ilan , Shia Jinru , Zeng Zhaoshi , Liu Hao , Krier Curtis , Stengel Robert F. , Barany Francis , Gerald William L. , Paty Philip B. , Domany Eytan , Notterman Daniel A.
Published: March 2023

Abstract
Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples. (Cancer Res 2006; 66(4): 2129-37)