bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epithelial to Mesenchymal Transition in Human Breast Epithelial Cells Transformed by 17β-Estradiol
Authors: Huang Yong , Fernandez Sandra V. , Goodwin Shirlean , Russo Patricia A. , Russo Irma H. , Sutter Thomas R. , Russo Jose 
Published: December 2007

Abstract
The estrogen dependence of breast cancer has long been recognized; however, the role of 17β-estradiol (E2) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E2 treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF &gt; bcMCF &gt;&gt;&gt; trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor β1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation. [Cancer Res 2007;67(23):11147–57]
Nuclear Factor-κB, an Unappreciated Tumor Suppressor
Authors: Chen Fei , Castranova Vince 
Published: December 2007

Abstract
The notion that nuclear factor-κB (NF-κB) is a tumor-promoting transcription factor has become a widely accepted dogma in biology. However, recent findings suggest an inhibitory role for NF-κB in carcinogenesis and tumorigenesis. Although the tumor suppressor–like effect of NF-κB remains to be rigorously established by further studies using cellular and animal models, these latest findings warrant caution with respect to blockage of NF-κB activation as a broad strategy in treating cancers. [Cancer Res 2007;67(23):11093–8]
The p38 MAPK Pathway Mediates Aryl Propionic Acid–Induced Messenger RNA Stability of p75NTR in Prostate Cancer Cells
Authors: Quann Emily J. , Khwaja Fatima , Djakiew Daniel 
Published: December 2007

Abstract
The p75NTR acts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75NTR expression in PC-3 and DU-145 cells leading to p75NTR-mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75NTR expression. We show that the observed increase in p75NTR protein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75NTR mRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK–specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75NTR by R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75NTR by R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75NTR expression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75NTR expression by increased mRNA stability that is mediated through the p38 MAPK pathway. [Cancer Res 2007;67(23):11402–10]
Amino-Biphosphonate–Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma
Authors: Melani Cecilia , Sangaletti Sabina , Barazzetta Francesca M. , Werb Zena , Colombo Mario P. 
Published: December 2007

Abstract
BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro–MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro–MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor–derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage. [Cancer Res 2007;67(23):11438–46]
Gpx2 Is an Overexpressed Gene in Rat Breast Cancers Induced by Three Different Chemical Carcinogens
Authors: Naiki-Ito Aya , Asamoto Makoto , Hokaiwado Naomi , Takahashi Satoru , Yamashita Hiroko , Tsuda Hiroyuki , Ogawa Kumiko , Shirai Tomoyuki 
Published: December 2007

Abstract
Gene expression alterations are essential for the process of carcinogenesis. A carcinogen may have specific mechanisms for inducing tumors, which may involve inducing characteristic gene expression alterations. In this study, we attempted to identify genes crucial for mammary carcinogenesis. For this purpose, we used human c-Ha-ras proto-oncogene transgenic rats (Hras128), which are highly sensitive to mammary carcinogens including N-methyl-N-nitrosourea, 7,12-dimethyl benz[a]anthracene, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. DNA microarray analysis revealed that glutathione peroxidase 2 (Gpx2) was commonly up-regulated in the mammary carcinomas induced by the three different carcinogens, and its up-regulation was confirmed by quantitative reverse transcriptase-PCR and Western blotting analysis. In addition, expression of GPX2 was recognized in all 41 immunohistochemically examined cases of human breast cancer. Forced suppression of GPX2 expression by siRNA resulted in significant growth inhibition in both rat and human mammary carcinoma cell lines with wild-type p53 cells. Thus, these data suggested that GPX2 may be involved in mammary carcinogenesis and cell proliferation in both rats and humans, indicating that GPX2 may be a novel target for the prevention and therapy of breast cancer. [Cancer Res 2007;67(23):11353–8]
The Novel Combination of Chlorpromazine and Pentamidine Exerts Synergistic Antiproliferative Effects through Dual Mitotic Action
Authors: Lee Margaret S. , Johansen Lisa , Zhang Yanzhen , Wilson Amy , Keegan Mitchell , Avery William , Elliott Peter , Borisy Alexis A. , Keith Curtis T. 
Published: December 2007

Abstract
Combination therapy has proven successful in treating a wide variety of aggressive human cancers. Historically, combination treatments have been discovered through serendipity or lengthy trials using known anticancer agents with similar indications. We have used combination high-throughput screening to discover the unexpected synergistic combination of an antiparasitic agent, pentamidine, and a phenothiazine antipsychotic, chlorpromazine. This combination, CRx-026, inhibits the growth of tumor cell lines in vivo more effectively than either pentamidine or chlorpromazine alone. Here, we report that CRx-026 exerts its antiproliferative effect through synergistic dual mitotic action. Chlorpromazine is a potent and specific inhibitor of the mitotic kinesin KSP/Eg5 and inhibits tumor cell proliferation through mitotic arrest and accumulation of monopolar spindles. Pentamidine treatment results in chromosomal segregation defects and delayed progression through mitosis, consistent with inhibition of the phosphatase of regenerating liver family of phosphatases. We also show that CRx-026 synergizes in vitro and in vivo with the microtubule-binding agents paclitaxel and vinorelbine. These data support a model where dual action of pentamidine and chlorpromazine in mitosis results in synergistic antitumor effects and show the importance of systematic screening for combinations of targeted agents. [Cancer Res 2007;67(23):11359–67]
Adaptor Protein LAPF Recruits Phosphorylated p53 to Lysosomes and Triggers Lysosomal Destabilization in Apoptosis
Authors: Li Nan , Zheng Yuanyuan , Chen Wei , Wang Chunmei , Liu Xingguang , He Weigang , Xu Hongmei , Cao Xuetao 
Published: December 2007

Abstract
Evidence suggests a functional association between the tumor suppressor p53 and apoptosis-involved organelle lysosome; however, the detailed mechanisms remain poorly understood. We recently reported that a lysosome-targeting protein, LAPF (lysosome-associated and apoptosis-inducing protein containing PH and FYVE domains), could initiate apoptosis of L929 cells through a lysosomal-mitochondrial pathway. In this study, we show that LAPF specifically interacted with phosphorylated p53 (Ser15/18) both in vitro and in vivo, which could be enhanced by apoptotic stimuli, such as tumor necrosis factor α (TNF-α) and ionizing irradiation. The PH domain of LAPF and the transactivation domain of p53 mediated the interaction between both molecules. Phosphorylated p53 (Ser15/18) could translocate to lysosomes before lysosomal membrane permeabilization (LMP) in LAPF-initiated and TNF-induced apoptosis. Silencing of LAPF expression abrogated lysosomal translocation of phosphorylated p53 (Ser15/18), whereas silencing of p53 expression had no effect on lysosomal translocation of LAPF. Similar to that of LAPF silencing, silencing of endogenous p53 expression in L929 cells could significantly impair TNF-α–induced LMP and apoptosis. However, reexpression of wild-type p53, p53S15D (substitution of Ser15 to Asp that mimics a phosphorylated state), and p53R175H (a transcription-deficient mutant) in p53-knockdown L929 cells could rescue the decrease in TNF-induced apoptosis. The data suggest that phosphorylated p53 (Ser15/18) might translocate to lysosome via forming complexes with adaptor protein LAPF and subsequently result in LMP and apoptosis, which might be in a transcription-independent manner. [Cancer Res 2007;67(23):11176–85]
Polo-like Kinase 1 Is Involved in Invasion through Extracellular Matrix
Authors: Rizki Aylin , Mott Joni D. , Bissell Mina J. 
Published: December 2007

Abstract
Polo-like kinase 1 (PLK1) has important functions in maintaining genome stability via its role in mitosis. Because PLK1 is up-regulated in many invasive carcinomas, we asked whether it may also play a role in acquisition of invasiveness, a crucial step in transition to malignancy. In a model of metaplastic basal-like breast carcinoma progression, we found that PLK1 expression is necessary but not sufficient to induce invasiveness through laminin-rich extracellular matrix. PLK1 mediates invasion via vimentin and β1 integrin, both of which are necessary. We observed that PLK1 phosphorylates vimentin on Ser82, which in turn regulates cell surface levels of β1 integrin. We found PLK1 to be also highly expressed in preinvasive in situ carcinomas of the breast. These results support a role for the involvement of PLK1 in the invasion process and point to this pathway as a potential therapeutic target for preinvasive and invasive breast carcinoma treatment. [Cancer Res 2007;67(23):11106–10]
Identification of Genes Required for Protection from Doxorubicin by a Genome-Wide Screen in Saccharomyces cerevisiae
Authors: Xia Ling , Jaafar Lahcen , Cashikar Anil , Flores-Rozas Hernan 
Published: December 2007

Abstract
Anthracyclines are chemotherapeutic agents commonly used to treat a broad range of malignancies. Although effective, these drugs present serious complications, most notably cardiotoxicity. To determine the mechanisms that mediate cytoprotection from doxorubicin, we have screened the collection of Saccharomyces cerevisiae haploid gene deletion mutants. We have identified 71 deletion strains that display varying degrees of hypersensitivity to doxorubicin at a concentration that does not significantly reduce the viability of wild-type cells. Complementation of the doxorubicin-sensitive phenotype of the deletion strains with the wild-type genes proves that the sensitivity of the strain to doxorubicin is due to the gene deletion. The genes that mediate cytoprotection from doxorubicin belong to multiple pathways including DNA repair, RNA metabolism, chromatin remodeling, amino acid metabolism, and heat shock response. In addition, proteins with mitochondrial, osmosensing, vacuolar, and ribosomal functions are also required for protection from doxorubicin. We tested the sensitivity of the deletion strains to other cytotoxic agents, which resulted in different drug-specific sensitive groups. Most of the identified genes have mammalian homologues that participate in conserved pathways. Our data may prove useful to develop strategies aimed at sensitizing tumor cells to doxorubicin as well as protecting cardiac cells from its cytotoxic effects. [Cancer Res 2007;67(23):11411–8]
Identification of Novel Modifier Loci of ApcMin Affecting Mammary Tumor Development
Authors: Wang Hua , Teske Douglas , Tess Alyssa , Kohlhepp Rebecca , Choi YounJeong , Kendziorski Christina , Moser Amy Rapaich 
Published: December 2007

Abstract
Genetic background affects the susceptibility to mammary tumor development in ApcMin/+ mice. Here we report the identification of four novel modifier loci that influence different aspects of mammary tumor development in ApcMin/+ mice. Analysis of tumor development in a backcross of (FVBB6 ApcMin/+) × B6 ApcMin/+ mice has identified a modifier on chromosome 9 that significantly affects tumor multiplicity, and a modifier on chromosome 4 that significantly affects tumor latency and affects tumor number with suggestive significance. This modifier was also identified in a backcross involving 129X1/SvJ and B6 ApcMin/+ mice. A modifier on chromosome 18 specifically affects tumor latency but not tumor number. Kaplan-Meier analysis suggests there is at least an additive interaction affecting tumor latency between the loci on chromosomes 4 and 18. We also identified a modifier locus on chromosome 6 that interacts with the loci on chromosome 4 and chromosome 9 to affect tumor number. These results suggest that multiple genetic loci control different aspects of mammary tumor development. None of these modifiers is associated with intestinal tumor susceptibility, which indicates that these modifiers act on tumor development in a tissue-specific manner. [Cancer Res 2007;67(23):11226–33]
The Guardian's Little Helper: MicroRNAs in the p53 Tumor Suppressor Network
Authors: He Xingyue , He Lin , Hannon Gregory J. 
Published: December 2007

Abstract
Several microRNAs (miRNAs) have been implicated in tumor development based on both changes in their expression patterns and gene structural alterations in human tumors. However, we are only now beginning to see how miRNAs interact with classic oncogene and tumor suppressor mechanisms. Several recent studies have implicated the miR-34 family of miRNAs in the p53 tumor suppressor network. The expression of miR-34a, miR-34b, and miR-34c is robustly induced by DNA damage and oncogenic stress in a p53-dependent manner. When overexpressed, miR-34 leads to apoptosis or cellular senescence, whereas reduction of miR-34 function attenuates p53-mediated cell death. These findings, together with the fact that miR-34 is down-regulated in several types of human cancer, show that miRNAs can affect tumorigenesis by working within the confines of well-known tumor suppressor pathways. [Cancer Res 2007;67(23):11099–101]
CD83 Gene Polymorphisms Increase Susceptibility to Human Invasive Cervical Cancer
Authors: Zhang Zhengyan , Borecki Ingrid , Nguyen Loan , Ma Duanduan , Smith Kimberly , Huettner Phyllis C. , Mutch David G. , Herzog Thomas J. , Gibb Randall K. , Powell Matthew A. , Grigsby Perry W. , Massad L. Stewart , Hernandez Enrique , Judson Patricia L. , Swisher Elizabeth M. , Crowder Sara , Li Jianduan , Gerhard Daniela S. , Rader Janet S. 
Published: December 2007

Abstract
We previously mapped a nonrandom frequent loss of heterozygosity (LOH) region in cervical cancers to 1 Mb of 6p23. Here, we describe the identification of a novel cervical cancer susceptibility gene, CD83. The gene was identified by several complementary approaches, including a family-based association study, comparison of transcript expression in normal and cancerous tissue, and genomic sequencing of candidate. CD83 encodes an inducible glycoprotein in the immunoglobulin superfamily and is a marker for mature dendritic cells. The association study that includes 377 family trios showed that five single nucleotide polymorphisms (SNP) within 8 kb of its 3′-end showed significant allelic association that was strengthened in a subgroup of women with invasive cancers infected by high-risk human papillomavirus type 16 and 18 (rs9296925, P = 0.0193; rs853360, P = 0.0035; rs9230, P = 0.0011; rs9370729, P = 0.0012; rs750749, P = 0.0133). Investigation of CD83 uncovered three alternative transcripts in cervical tissue and cell lines, with variant 3 (lacking exons 3 and 4) being more frequent in cervical cancer than in normal cervical epithelium (P = 0.0181). Genomic sequencing on 36 paired normal and cervical tumors revealed several somatic mutations and novel SNPs in the promoter, exons, and introns of CD83. LOH was confirmed in &gt;90% of cervical cancer specimens. Immunofluorescence colocalized CD83 protein to the Golgi apparatus and cell membrane of cervical cancer cell lines. None of seven nearby genes was differentially expressed in cervical cancer. The importance of CD83 in epithelial versus dendritic cells needs to be determined, as does its role in promoting cervical cancer. [Cancer Res 2007;67(23):11202–8]
Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde
Authors: Ridpath John R. , Nakamura Ayumi , Tano Keizo , Luke April M. , Sonoda Eiichiro , Arakawa Hiroshi , Buerstedde Jean-Marie , Gillespie David A.F. , Sale Julian E. , Yamazoe Mitsuyoshi , Bishop Douglas K. , Takata Minoru , Takeda Shunichi , Watanabe Masami , Swenberg James A. , Nakamura Jun 
Published: December 2007

Abstract
Formaldehyde is an aliphatic monoaldehyde and is a highly reactive environmental human carcinogen. Whereas humans are continuously exposed to exogenous formaldehyde, this reactive aldehyde is a naturally occurring biological compound that is present in human plasma at concentrations ranging from 13 to 97 μmol/L. It has been well documented that DNA-protein crosslinks (DPC) likely play an important role with regard to the genotoxicity and carcinogenicity of formaldehyde. However, little is known about which DNA damage response pathways are essential for cells to counteract formaldehyde. In the present study, we first assessed the DNA damage response to plasma levels of formaldehyde using chicken DT40 cells with targeted mutations in various DNA repair genes. Here, we show that the hypersensitivity to formaldehyde is detected in DT40 mutants deficient in the BRCA/FANC pathway, homologous recombination, or translesion DNA synthesis. In addition, FANCD2-deficient DT40 cells are hypersensitive to acetaldehyde, but not to acrolein, crotonaldehyde, glyoxal, and methylglyoxal. Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels of formaldehyde. These results indicate that the BRCA/FANC pathway is essential to counteract DPCs caused by aliphatic monoaldehydes. Based on the results obtained in the present study, we are currently proposing that endogenous formaldehyde might have an effect on highly proliferating cells, such as bone marrow cells, as well as an etiology of cancer in Fanconi anemia patients. [Cancer Res 2007;67(23):11117–22]
Inhibition of the Intrinsic Apoptosis Pathway Downstream of Caspase-9 Activation Causes Chemotherapy Resistance in Diffuse Large B-Cell Lymphoma
Authors: Cillessen Saskia A.G.M. , Hess Corine J. , Hooijberg Erik , Castricum Kitty C.M. , Kortman Pim , Denkers Fedor , Vos Wim , van de Wiel Mark A. , Schuurhuis Gerrit J. , Ossenkoppele Gert J. , Meijer Chris J.L.M. , Oudejans Joost J. 
Published: December 2007

AbstractPurpose: Inhibition of the apoptosis cascade is an important cause of therapy resistance in diffuse large B-cell lymphomas (DLBCL). In this study, we investigated possible mechanisms and expression levels of apoptosis-related genes in the apoptosis pathway that may be responsible for differences in chemotherapy sensitivity between DLBCL patients.Experimental Design: Twenty-eight DLBCL patient samples were investigated for their expression levels of apoptosis-related genes using reverse transcription-multiplex ligation-dependent probe amplification analysis. Functional analysis of the intrinsic, caspase-9–mediated pathway was done using fluorescence-activated cell sorting analysis, Western blot analysis, and immunohistochemistry.Results: Two DLBCL groups were identified: one with low expression levels of both proapoptotic and antiapoptotic genes and one group with high expression levels of these genes. DLBCL with high expression levels of proapoptotic and antiapoptotic genes frequently seemed to be refractory to clinical chemotherapy. Functional analysis in these latter DLBCL samples and DLBCL cell lines with comparable expression profiles revealed high levels of spontaneous caspase-9 activity without induction of apoptosis, indicating disruption of the apoptosis pathway downstream of caspase-9 activation. This disruption of the apoptosis pathway could be restored using a small-molecule XIAP antagonist.Conclusions: We conclude that the intrinsic, caspase-9–mediated apoptosis pathway is constitutively activated in part of chemotherapy-refractory DLBCL with concomitant downstream inhibition of the convergence apoptosis pathway and that inhibition of XIAP might be an alternative therapy for chemotherapy-refractory DLBCL.