bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variation in the One-Carbon Transfer Pathway and Ovarian Cancer Risk
Authors: Kelemen Linda E. , Sellers Thomas A. , Schildkraut Joellen M. , Cunningham Julie M. , Vierkant Robert A. , Pankratz V. Shane , Fredericksen Zachary S. , Gadre Madhura K. , Rider David N. , Liebow Mark , Goode Ellen L. 
Published: April 2008

Abstract
Dysfunction in enzymes involved in one-carbon (1-C) metabolism can lead to increased chromosomal strand breaking and abnormal methylation patterns, which are both associated with cancer risk. Availability of 1-C units may modify risk. We investigated the association of single-nucleotide polymorphisms (SNP) in 21 genes in the 1-C transfer pathway among 829 Caucasian cases with primary epithelial ovarian cancer and 941 frequency-matched unaffected controls enrolled at Mayo Clinic (Rochester, MN) and Duke University (Durham, NC) and examined risk modification by multivitamin supplement use. Multivariable-adjusted SNP-specific logistic regression and haplotype analyses were done for 180 SNPs and false positive report probabilities (FPRP) were calculated. Each copy of the minor allele in SHMT1 intron 5 A&gt;G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0–1.4; P trend = 0.02; FPRP = 0.16] and a 5-SNP SHMT1 haplotype was associated with decreased risk (P = 0.01; FPRP = 0.09). Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3′ untranslated region (UTR) C&gt;G (rs13420827: OR, 0.8; 95% CI, 0.6–1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G&gt;A (rs11887120: OR, 0.8; 95% CI, 0.7–1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A&gt;T (rs11695471: OR, 1.2; 95% CI, 1.0–1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk. [Cancer Res 2008;68(7):2498–506]
Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α5-Integrin, which Is a Therapeutic Target
Authors: Sawada Kenjiro , Mitra Anirban K. , Radjabi A. Reza , Bhaskar Vinay , Kistner Emily O. , Tretiakova Maria , Jagadeeswaran Sujatha , Montag Anthony , Becker Amy , Kenny Hilary A. , Peter Marcus E. , Ramakrishnan Vanitha , Yamada S. Diane , Lengyel Ernst 
Published: April 2008

Abstract
E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of α5-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an α5β1-integrin–blocking antibody. When E-cadherin is silenced, α5-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1–mitogen-activated protein kinase–dependent signaling pathway and not through the canonical E-cadherin/β-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of α5-integrin, i.p. treatment with an α5β1-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P &lt; 0.0005). α5-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had α5-integrin overexpression, and 39% had some level of α5-integrin expression. The median survival for patients with high α5-integrin levels was 26 months versus 35 months for those with low integrin expression (P &lt; 0.05). Taken together, we have identified α5-integrin up-regulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. [Cancer Res 2008;68(7):2329–39]
Epidermal Growth Factor Receptor Gene Amplification Is Acquired in Association with Tumor Progression of EGFR-Mutated Lung Cancer
Authors: Yatabe Yasushi , Takahashi Takashi , Mitsudomi Tetsuya 
Published: April 2008

Abstract
Both mutation and amplification of epidermal growth factor receptor (EGFR) in lung cancers have been reported in association with clinical responses to tyrosine kinase inhibitors. We have reported evidence implicating mutation specifically in the “terminal respiratory unit” type of adenocarcinoma, which is characterized by expression of thyroid transcription factor 1, a lineage marker of peripheral airway cells. However, little is known about the role of gene amplification in the molecular progression of lung adenocarcinoma. In this study, we examined the topographical distribution of amplification in three microdissected portions each of 48 individual lung cancers with confirmed mutations. Relative copy number of the gene was analyzed using Taq Man–based gene dosage analysis and fluorescent in situ hybridization technique. Gene amplification was found in 11 lung cancers. Strikingly, nine of the cancers showed heterogeneous distribution, and amplification was associated with higher histologic grade or invasive growth. Because it was likely that the high-grade lesions were the origin for metastases, metastatic lymph nodes corresponding to five tumors with heterogeneous distribution were analyzed. Unexpectedly, amplification status of the metastatic sites was not always associated with gene amplification of the primary tumors, suggesting that selection of the metastatic clone may be defined by other factors. We also examined 17 precursor lesions and 21 in situ lung adenocarcinomas, and found that only one in situ carcinoma harbored gene amplification. Taken together, our results show that mutation occurs early in the development of lung adenocarcinoma, and that amplification may be acquired in association with tumor progression. [Cancer Res 2008;68(7):2106–11]
Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2
Authors: Lin Yi-Chu , Lin Jung-Hsin , Chou Chia-Wei , Chang Yu-Fan , Yeh Shu-Hao , Chen Ching-Chow 
Published: April 2008

Abstract
Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers. In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21WAF/CIP in human cancer cells. Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a Ki value of 31.6 μmol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays. DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter. In vitro cell proliferation and in vivo tumor growth were both inhibited by statins. These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression. Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention. [Cancer Res 2008;68(7):2375–83]
An Effective Vaccine Strategy Protective against Antigenically Distinct Tumor Variants
Authors: Pavelko Kevin D. , Heckman Karin L. , Hansen Michael J. , Pease Larry R. 
Published: April 2008

Abstract
Antigenically distinct tumor variants can emerge in response to selective pressures inherent to host-tumor interactions. The development of successful immunotherapeutic strategies can be limited by these disparate antigenic profiles. Using the immunomodulator B7-DC XAb to activate cytolytic T cells specific for tumor-associated antigens, we found that the specificity of immune responses elicited by live tumors are distinct from the specificity of the responses elicited by soluble proteins derived from the same tumors. Remarkably, whereas the induced antitumor immunity generated against live variants of the B16 melanoma and EL4 thymic lymphoma tumors were highly specific for the original tumor variant used in the challenge, immunity generated using soluble proteins derived from tumor lysates was broadly reactive, recognizing the challenge tumor, as well as antigenically distinct variants. The antigens detected using live tumor and tumor lysate vaccines could be distinguished biochemically, demonstrating that they are structurally distinct. We show that vaccines using antigens present in tumor cell lysates induce protective immunity with strong memory against distantly related tumor variants. The existence of a class of antigens shared among tumor variants provides an attractive target for vaccine development. [Cancer Res 2008;68(7):2471–8]
Evaluation of Genetic Variants in MicroRNA-Related Genes and Risk of Bladder Cancer
Authors: Yang Hushan , Dinney Colin P. , Ye Yuanqing , Zhu Yong , Grossman H. Barton , Wu Xifeng 
Published: April 2008

Abstract
MicroRNAs (miRNA) are small noncoding RNA molecules involved in a diversity of cellular functions. Although it has been reported that global suppression of the miRNA biogenesis pathway leads to enhanced tumorigenesis, the effect of common genetic variants of miRNA-related genes on cancer predisposition is unclear. To better understand this effect, we genotyped 41 single-nucleotide polymorphisms (SNP) from 24 miRNA-related genes in a case-control study conducted in 746 Caucasian patients with bladder cancer and 746 matched controls. The homozygous variant genotype of a nonsynonymous SNP in the GEMIN3 gene (rs197414) was associated with a significantly increased bladder cancer risk [odds ratios (OR), 2.40; 95% confidence interval (95% CI), 1.04–5.56]. Several additional miRNA-related SNPs were also identified that showed a borderline significant association with bladder cancer risk. Haplotype analysis indicated that a common haplotype of the GEMIN4 gene was associated with a significantly increased bladder cancer risk with an OR of 1.25 (95% CI, 1.01–1.54). To assess the aggregate effects of the promising SNPs, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. We found that, compared with the low-risk reference group with less than two unfavorable genotypes, the medium-risk group with two unfavorable genotypes exhibited a 1.29-fold (0.92–1.81) increased risk whereas the high-risk group with more than two unfavorable genotypes exhibited a 1.92-fold (1.36–2.71) increased risk (Ptrend &lt; 0.0001). Overall, this is the first epidemiologic study showing that miRNA-related genetic variants may affect bladder cancer risk individually and jointly. [Cancer Res 2008;68(7):2530–7]
Activator Protein-1 Transcription Factors Are Associated with Progression and Recurrence of Prostate Cancer
Authors: Ouyang Xuesong , Jessen Walter J. , Al-Ahmadie Hikmat , Serio Angel M. , Lin Yong , Shih Weichung-Joseph , Reuter Victor E. , Scardino Peter T. , Shen Michael M. , Aronow Bruce J. , Vickers Andrew J. , Gerald William L. , Abate-Shen Cory 
Published: April 2008

Abstract
To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors—the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer. [Cancer Res 2008;68(7):2132–44]
Down-regulation of Mammalian Sterile 20–Like Kinase 1 by Heat Shock Protein 70 Mediates Cisplatin Resistance in Prostate Cancer Cells
Authors: Ren Aixia , Yan Guijun , You Bei , Sun Jianxin 
Published: April 2008

Abstract
Mammalian sterile 20–like kinase 1 (Mst1) is an ubiquitously expressed serine/threonine kinase, and its activation results in cell apoptosis. Recent studies suggest that Mst1 may function as a tumor suppressor. Here, we reported that heat shock protein 70 (Hsp70), which is thought to protect cells against cellular stress, has been identified as an Mst1-interacting protein, in a yeast two-hybrid screen of human adult prostate cDNA library with a dominant-negative Mst1 (K59R) as bait. The interaction of Mst1 with Hsp70 was confirmed by coimmunoprecipitation in both cotransfected HEK293 cells and prostate cancer cells. Hsp70 colocalized with Mst1 in the cytoplasm of LNCaP cells. The interaction sites with Mst1 consisted of NH2-terminal ATPase domain in Hsp70, whereas the inhibitory domain of Mst1 mediates the binding of Hsp70 in Mst1. Overexpression of Hsp70 mediates proteasomal degradation of Mst1 in a Hsp70 interacting protein (CHIP)-dependent manner. Furthermore, the proapoptotic effect of Mst1 was markedly inhibited by overexpression of Hsp70 or CHIP. Most strikingly, in response to the treatment of anticancer drug cisplatin, the induction of Hsp70 expression is higher in the androgen-independent DU145 cells compared with the androgen-dependent LNCaP cells. The higher levels of Hsp70 induction and subsequent Mst1 degradation mediate cisplatin resistance in prostate cancer DU145 cells. Moreover, overexpression of Mst1 sensitizes prostate cancer cells to cisplatin treatment. These findings implicate that Mst1, a downstream target of Hsp70, may be developed as a target for sensitizing hormone-refractory prostate cancers to chemotherapy. [Cancer Res 2008;68(7):2266–74]
A Novel Lung Cancer Signature Mediates Metastatic Bone Colonization by a Dual Mechanism
Authors: Vicent Silvestre , Luis-Ravelo Diego , Antón Iker , García-Tuñón Ignacio , Borrás-Cuesta Francisco , Dotor Javier , De Las Rivas Javier , Lecanda Fernando 
Published: April 2008

Abstract
Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. To identify and functionally characterize genes involved in the mechanisms of osseous metastasis, we developed a murine lung cancer model. Comparative transcriptomic analysis identified genes encoding signaling molecules (such as TCF4 and PRKD3) and cell anchorage–related proteins (MCAM and SUSD5), some of which were basally modulated by transforming growth factor-β (TGF-β) in tumor cells and in conditions mimicking tumor-stromal interactions. Triple gene combinations induced not only high osteoclastogenic activity but also a marked enhancement of global metalloproteolytic activities in vitro. These effects were strongly associated with robust bone colonization in vivo, whereas this gene subset was ineffective in promoting local tumor growth and cell homing activity to bone. Interestingly, global inhibition of metalloproteolytic activities and simultaneous TGF-β blockade in vivo led to increased survival and a remarkable attenuation of bone tumor burden and osteolytic metastasis. Thus, this metastatic gene signature mediates bone matrix degradation by a dual mechanism of induction of TGF-β–dependent osteoclastogenic bone resorption and enhancement of stroma-dependent metalloproteolytic activities. Our findings suggest the cooperative contribution of host-derived and cell autonomous effects directed by a small subset of genes in mediating aggressive osseous colonization. [Cancer Res 2008;68(7):2275–85]
Enhancing Poxvirus Oncolytic Effects through Increased Spread and Immune Evasion
Authors: Kirn David H. , Wang Yaohe , Liang Wenchung , Contag Christopher H. , Thorne Stephen H. 
Published: April 2008

Abstract
The antitumoral effects of oncolytic viruses have generally been limited by inefficient spread of the viruses within infected tumors and by inefficient systemic delivery, particularly in preimmunized hosts. Tumor-selective poxviruses have biological characteristics that may overcome these limitations. Nevertheless, physical barriers within the tumor microenvironment, including the extracellular matrix, can still limit intratumoral spread, and neutralizing antibodies can impede systemic delivery. To counter these limitations, we sought to take advantage of a naturally occurring poxvirus form known as extracellular enveloped virus (EEV). The EEV is shrouded by a host cell–derived lipid bilayer containing anticomplement proteins and is typically released from infected cells early during the infection cycle. Therefore, the EEV form evolved for rapid systemic spread within the host and for evasion of immune-mediated clearance. We compared the oncolytic potential of low versus high EEV-producing strains of vaccinia. EEV-enhanced vaccinia strains displayed improved spread within tumors after systemic delivery, resulting in significantly improved antitumor effects. The EEV-enhanced strains also displayed a greater ability to spread between injected and noninjected distant tumors through the blood and, importantly, displayed reduced clearance by neutralizing antibody. Safety was unaffected. The incorporation of EEV-enhancing mutations into next generation oncolytic vaccinia strains may improve the potency of these viruses without sacrificing safety. [Cancer Res 2008;68(7):2071–5]
Bisphenol A Induces a Profile of Tumor Aggressiveness in High-Risk Cells from Breast Cancer Patients
Authors: Dairkee Shanaz H. , Seok Junhee , Champion Stacey , Sayeed Aejaz , Mindrinos Michael , Xiao Wenzhong , Davis Ronald W. , Goodson William H. 
Published: April 2008

Abstract
Breast cancer outcome is highly variable. Whether inadvertent exposure to environmental xenobiotics evokes a biological response promoting cancer aggressiveness and a higher probability of tumor recurrence remains unknown. To determine specific molecular alterations which arise in high-risk breast tissue in the presence of the ubiquitous xenoestrogen, bisphenol A (BPA), we used nonmalignant random periareolar fine-needle aspirates in a novel functional assay. Early events induced by BPA in epithelial-stromal cocultures derived from the contralateral tissue of patients with breast cancer included gene expression patterns which facilitate apoptosis evasion, endurance of microenvironmental stress, and cell cycle deregulation without a detectable increase in cell numbers. This BPA response profile was significantly associated with breast tumors characterized by high histologic grade (P &lt; 0.001) and large tumor size (P = 0.002), resulting in decreased recurrence-free patient survival (P &lt; 0.001). Our assays show a biological “fingerprint” of probable prior exposure to endocrine-disrupting agents, and suggest a scenario in which their presence in the microenvironmental milieu of high-risk breast tissue could play a deterministic role in establishing and maintaining tumor aggressiveness and poor patient outcome. [Cancer Res 2008;68(7):2076–80]
Development of Novel Tetravalent Anti-CD20 Antibodies with Potent Antitumor Activity
Authors: Li Bohua , Shi Shu , Qian Weizhu , Zhao Lei , Zhang Dapeng , Hou Sheng , Zheng Lei , Dai Jianxin , Zhao Jian , Wang Hao , Guo Yajun 
Published: April 2008

AbstractDespite the effectiveness of the anti-CD20 monoclonal antibody (mAb) Rituximab (C2B8) in the treatment of B-cell lymphoma, its efficacy remains variable and often modest. It seems likely that a combination of multiple mechanisms, such as complement-dependent cytotoxicity (CDC) and apoptotic signaling, underlies the therapeutic success of anti-CD20 mAbs. Unfortunately, all the current anti-CD20 mAbs effective in CDC are relatively inactive in signaling cell death and vice versa. In this study, we developed two genetically engineered tetravalent antibodies (TetraMcAb) respectively derived from the anti-CD20 mAbs C2B8 and 2F2. TetraMcAbs, with a molecular mass only 25 kDa higher than native divalent antibodies (DiMcAb), were shown not only to be as effective in mediating CDC and antibody-dependent cellular cytotoxicity against B-lymphoma cells as DiMcAbs but also to have antiproliferative and apoptosis-inducing activity markedly superior to that of DiMcAbs. Interestingly, whereas 2F2 and C2B8 were equally effective in inducing cell growth arrest and apoptosis, the functions of their tetravalent versions, 2F2(ScFvHL)4-Fc and C2B8(ScFvHL)4-Fc, were significantly different. 2F2(ScFvHL)4-Fc exhibited exceptionally more potent antiproliferative and apoptosis-inducing activity than that of C2B8(ScFvHL)4-Fc. Immunotherapeutic studies further showed that 2F2(ScFvHL)4-Fc was far more effective in prolonging the survival of severe combined immunodeficient mice bearing systemic Daudi or Raji tumors than C2B8, 2F2, and C2B8(ScFvHL)4-Fc, suggesting that it might be a promising therapeutic agent for B-cell lymphoma. [Cancer Res 2008;68(7):2400–8]