bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population-Based Study of Natural Variation in the Melanocortin-1 Receptor Gene and Melanoma
Authors: Kanetsky Peter A. , Rebbeck Timothy R. , Hummer Amanda J. , Panossian Saarene , Armstrong Bruce K. , Kricker Anne , Marrett Loraine D. , Millikan Robert C. , Gruber Stephen B. , Culver Hoda Anton , Zanetti Roberto , Gallagher Richard P. , Dwyer Terence , Busam Klaus , From Lynn , Mujumdar Urvi , Wilcox Homer , Begg Colin B. , Berwick Marianne ,   for the Genes Environment and Melanoma Study Group
Published: September 2006

Abstract
Natural variation in the coding region of the melanocortin-1 receptor (MC1R) gene is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. We investigated the effect of MC1R variants on melanoma using a large, international population-based study design with complete determination of all MC1R coding region variants. Direct sequencing was completed for 2,202 subjects with a single primary melanoma (controls) and 1,099 subjects with second or higher-order primary melanomas (cases) from Australia, the United States, Canada, and Italy. We observed 85 different MC1R variants, 10 of which occurred at a frequency &gt;1%. Compared with controls, cases were more likely to carry two previously identified red hair (“R”) variants [D84E, R151C, R160W, and D294H; odds ratio (OR), 1.6; 95% confidence interval (95% CI), 1.1-2.2]. This effect was similar among individuals carrying one R variant and one r variant (defined as any non-R MC1R variant; OR, 1.6; 95% CI, 1.3-2.2) and among those carrying only one R variant (OR, 1.5; 95% CI, 1.1-1.9). There was no statistically significant association among those carrying only one or two r variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low-penetrance susceptibility locus for melanoma, show that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported in part due to the study design. (Cancer Res 2006; 66(18): 9330-7)
Inhibition of Mitogen-Elicited Signal Transduction and Growth in Prostate Cancer with a Small Peptide Derived from the Functional Domain of DOC-2/DAB2 Delivered by a Unique Vehicle
Authors: Zhou Jian , Fan Jinhai , Hsieh Jer-Tsong 
Published: September 2006

Abstract
Differentially expressed in ovarian cancer-2/disabled 2 (DOC-2/DAB2) protein, often lost in prostate cancer and other cancer types, is a part of homeostatic machinery in normal prostate epithelium. DOC-2/DAB2 modulates mitogen-elicited mitogen-activated protein kinase (MAPK) signal transduction by sequestering several adaptor or effector molecules, such as growth factor receptor bound protein 2 and c-Src. We have shown that the proline-rich sequence in DOC-2/DAB2 is the key functional domain for this action. In this study, we further synthesized peptide based on the functional proline-rich domain and examined its biological function in prostate cancer using cell-permeable peptide (CPP) as a delivery system. From screening of several CPPs in prostate cancer cell lines, a polyarginine peptide (R11) seemed to be the best delivery vehicle because of its highly efficient uptake. In addition, we also observed a similar in vitro half-life and cellular location of R11 in four different prostate cancer cell lines. By conjugating a proline-rich sequence (PPL) or control sequence (AAL) derived from DOC-2/DAB2 to the COOH terminus of R11, we showed that R11PPL but not R11 or R11AAL was able to suppress either serum- or androgen-induced cell proliferation in prostate cancer cells without endogenous DOC-2/DAB2 expression. Consistently, the activation status of MAPK elicited by these mitogens was significantly inhibited by R11PPL but not by R11AAL or R11. Taken together, we conclude that a functional peptide derived from proline-rich domain in DOC-2/DAB2 has growth-inhibitory activity as its native protein, and CPP seems to be an efficient delivery system in prostate cancer cells. (Cancer Res 2006; 66(18): 8954-8)
Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells
Authors: Cai Dongpo , Latham Vaughan M. , Zhang Xinxin , Shapiro Geoffrey I. 
Published: September 2006

AbstractSelective cyclin-dependent kinase (cdk) 2 inhibition is readily compensated. However, reduced cdk2 activity may have antiproliferative effects in concert with other family members. Here, inducible RNA interference was used to codeplete cdk2 and cdk1 from NCI-H1299 non–small cell lung cancer and U2OS osteosarcoma cells, and effects were compared with those mediated by depletion of either cdk alone. Depletion of cdk2 slowed G1 progression of NCI-H1299 cells and depletion of cdk1 slowed G2-M progression in both cell lines, with associated endoreduplication in U2OS cells. However, compared with the incomplete cell cycle blocks produced by individual depletion, combined depletion had substantial consequences, with G2-M arrest predominating in NCI-H1299 cells and apoptosis the primary outcome in U2OS cells. In U2OS cells, combined depletion affected RNA polymerase II expression and phosphorylation, causing decreased expression of the antiapoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis (XIAP), effects usually mediated by inhibition of the transcriptional cdk9. These events do not occur after individual depletion of cdk2 and cdk1, suggesting that reduction of cdk2, cdk1, and RNA polymerase II activities all contribute to apoptosis in U2OS cells. The limited cell death induced by combined depletion in NCI-H1299 cells was significantly increased by codepletion of cdk9 or XIAP or by simultaneous treatment with the cdk9 inhibitor flavopiridol. These results show the potency of concomitant compromise of cell cycle and transcriptional cdk activities and may guide the selection of clinical drug candidates. (Cancer Res 2006; 66(18): 9270-80)
Estrogen Receptor Positive Breast Cancer Metastasis: Altered Hormonal Sensitivity and Tumor Aggressiveness in Lymphatic Vessels and Lymph Nodes
Authors: Harrell Joshua Chuck , Dye Wendy W. , Allred D. Craig , Jedlicka Paul , Spoelstra Nicole S. , Sartorius Carol A. , Horwitz Kathryn B. 
Published: September 2006

Abstract
Breast cancers commonly spread to lymph nodes (LNs). If the primary tumors are estrogen receptor (ER) and/or progesterone receptor (PR) positive, then the likelihood that LN metastases express receptors exceeds 80%. However, due to lack of ER+ models, little is known about the role of hormones in breast cancer spread or the effects of the LN microenvironment on hormone responsiveness. We have developed metastasis models using ZsGreen labeled MCF-7 and T47D human breast cancer cells. Tumors are tracked in living mice by whole-body imaging, and macrometastases or micrometastases are detected by intravital imaging or fluorescence microscopy. Tumor growth is estrogen dependent and required for intratumoral lymphangiogenesis. Seventy-five percent of all tumors and &gt;95% of larger tumors generate LN metastases. Occasionally more distant metastases are also observed. “Triads” of primary tumors, tumor-filled draining lymphatic vessels, and tumor-filled LNs from the same mouse show that (a) proliferation, as measured by 5-bromo-2′-deoxyuridine uptake, is higher in the LN than in the primary tumor. (b) High ER levels are extensively down-regulated by estradiol in primary tumors. However, there is partial failure of ER down-regulation in LNs associated with (c) reduced PR expression. This suggests that ER are dysfunctional in the LN microenvironment and perhaps hormone resistant. (d) CD44 is sparsely expressed in primary tumor cells but homogeneously overexpressed in cells transiting the lymphatics and populating LNs. We hypothesize that CD44 expression targets tumor cells for transport to, and uptake in, LNs. If so, the CD44 pathway could be targeted therapeutically to slow or prevent LN metastases. (Cancer Res 2006; 66(18): 9308-15)
Human Tumor-Released Microvesicles Promote the Differentiation of Myeloid Cells with Transforming Growth Factor-β–Mediated Suppressive Activity on T Lymphocytes
Authors: Valenti Roberta , Huber Veronica , Filipazzi Paola , Pilla Lorenzo , Sovena Gloria , Villa Antonello , Corbelli Alessandro , Fais Stefano , Parmiani Giorgio , Rivoltini Licia 
Published: September 2006

AbstractHuman tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR−/low cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-α, and transforming growth factor-β (TGF-β), and a dose-dependent suppressive activity on activated T-cell–proliferation and cytolytic functions, which could be reversed by anti-TGF-β–neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14+ monocytes, skewing their differentiation toward CD14+HLA-DR−/low cells with TGF-β–mediated suppressive activity on T-cell–functions. Interestingly, a subset of TGF-β–secreting CD14+HLA-DR− cells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell–mediated control of tumor growth in cancer patients. (Cancer Res 2006; 66(18): 9290-8)
Interplay between Notch Signaling and Epigenetic Silencers in Cancer
Authors: Dominguez Maria 
Published: September 2006

Abstract
Given its role in the development and self-renewal of many tissues, it is not surprising that a prominent role has recently been proposed for the Notch signal transduction pathway in tumor development. However, exactly how Notch hyperactivation promotes oncogenesis is poorly understood. Recent findings in Drosophila melanogaster have linked the Notch pathway to epigenetic silencing and the tumor suppressor gene Rb during tumorigenesis. Because aberrant epigenetic gene silencing contributes to the pathogenesis of most human cancers, these findings may provide a new focal point to understand how Notch is associated with cancers, and to help develop better selective cancer therapies. (Cancer Res 2006; 66(18): 8931-4)
A Human Cell-Based Assay to Evaluate the Effects of Alterations in the MLH1 Mismatch Repair Gene
Authors: Blasi Monica Francesca , Ventura Ilenia , Aquilina Gabriele , Degan Paolo , Bertario Lucio , Bassi Chiara , Radice Paolo , Bignami Margherita 
Published: September 2006

Abstract
We describe a new approach to investigate alterations in the human MLH1 mismatch repair (MMR) gene. This is based on complementation of the phenotype of a MLH1-defective subclone of the ovarian carcinoma A2780 cells by transfection of vectors encoding altered MLH1 proteins. Measurements of resistance (tolerance) to methylating agents, mutation rate at HPRT, microsatellite instability (MSI), and steady-state levels of DNA 8-oxoguanine were used to define the MMR status of transfected clones. The approach was validated by transfecting cDNA of wild-type (WT) MLH1, cDNAs bearing two previously identified polymorphisms (I219V and I219L) and two with confirmed hereditary nonpolyposis colorectal cancer (HNPCC) syndrome mutations (G224D and G67R). A low-level expression of two MLH1 polymorphisms partially reversed methylation tolerance and the mutator phenotype, including MSI. Higher levels of I219V resulted in full restoration of these properties to WT. Increased expression of I129L did not fully complement the MLH1 defect, because there was a simultaneous escalation in the level of oxidative DNA damage. The findings confirmed the important relationship between deficient MMR and increased levels of oxidative DNA damage. Mutations from Italian HNPCC families (G224D, G67R, N635S, and K618A) were all ineffective at reversing the phenotype of the MLH1-defective A2780 cells. One (K618A) was identified as a low penetrance mutation based on clinical and genetic observations. (Cancer Res 2006; 66(18): 9036-44)
The Corepressor Silencing Mediator for Retinoid and Thyroid Hormone Receptor Facilitates Cellular Recovery from DNA Double-Strand Breaks
Authors: Yu Jiujiu , Palmer Christine , Alenghat Theresa , Li Yun , Kao Gary , Lazar Mitchell A. 
Published: September 2006

Abstract
Cells are frequently challenged by DNA double-strand breaks (DSB) that threaten their normal function and survival. In mammalian cells, the repair of DSBs is predominantly mediated by the DNA-dependent protein kinase (DNA-PK) complex. We unexpectedly found that the corepressor silencing mediator for retinoid and thyroid hormone receptor (SMRT) associates with the DNA-PK repair complex. The SMRT/histone deacetylase 3 complex is required for the transcriptional repressive property of the Ku70 subunit of the repair complex. Moreover, SMRT, but not the related Nuclear Receptor Corepressor, is required for cellular recovery from DNA DSBs induced by ionizing radiation or DNA damage–inducing drugs. Thus, the corepressor SMRT plays a novel and critical role in the cellular response to DSBs. (Cancer Res 2006; 66(18): 9316-22)
Alteration of the Methylation Status of Tumor-Promoting Genes Decreases Prostate Cancer Cell Invasiveness and Tumorigenesis In vitro and In vivo
Authors: Shukeir Nicholas , Pakneshan Pouya , Chen Gaoping , Szyf Moshe , Rabbani Shafaat A. 
Published: September 2006

Abstract
We tested the hypothesis that cell invasiveness and tumorigenesis are driven by hypomethylation of genes involved in tumor progression. Highly invasive human prostate cancer cells PC-3 were treated with either the methyl donor S-adenosylmethionine (SAM) or methyl DNA-binding domain protein 2 antisense oligonucleotide (MBD2-AS). Both treatments resulted in a dose- and time-dependent inhibition of key genes, such as urokinase-type plasminogen activator (uPA), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor expression to decrease tumor cell invasion in vitro. No change in the levels of expression of genes already known to be methylated in late-stage prostate cancer cells, such as glutathione S-transferase P1 and androgen receptor, was seen. Inoculation of PC-3 cells pretreated with SAM and MBD2-AS into the flank of male BALB/c nu/nu mice resulted in the development of tumors of significantly smaller volume compared with animals inoculated with PC-3 cells treated with vehicle alone or MBD2 scrambled oligonucleotide. Immunohistochemical analysis of tumors showed the ability of SAM and MBD2-AS to significantly decrease tumoral uPA and MMP-2 expression along with levels of angiogenesis and survival pathway signaling molecules. Bisulfite sequencing analysis of tumoral genomic DNA showed that inhibition of both uPA and MMP-2 expression was due to methylation of their 5′ regulatory region. These studies support the hypothesis that DNA hypomethylation controls the activation of multiple tumor-promoting genes and provide valuable insight into developing novel therapeutic strategies against this common disease, which target the demethylation machinery. (Cancer Res 2006; 66(18): 9202-10)
Array Comparative Genomic Hybridization Reveals Distinct DNA Copy Number Differences between Gastrointestinal Stromal Tumors and Leiomyosarcomas
Authors: Meza-Zepeda Leonardo A. , Kresse Stine H. , Barragan-Polania Ana H. , Bjerkehagen Bodil , Ohnstad Hege O. , Namløs Heidi M. , Wang Junbai , Kristiansen Bjørn E. , Myklebost Ola 
Published: September 2006

Abstract
Leiomyosarcomas are spindle cell tumors showing smooth muscle differentiation. Until recently, most gastrointestinal stromal tumors (GIST) were also classified as smooth muscle tumors, but now GISTs are recognized as a separate entity, defined as spindle cell and/or epithelioid tumors localized in the gastrointestinal tract. Using microarray-based comparative genomic hybridization (array CGH), we have created a detailed map of DNA copy number changes for 7 GISTs and 12 leiomyosarcomas. Considerable gains and losses of chromosomal segments were observed in both tumor types. The most frequent aberration observed in GISTs was loss of chromosomes 14 and 22, with minimal recurrent regions in 14q11.2-q32.33 (71% of the tumors) and 22q12.2-q13.31 (100%). In leiomyosarcomas, frequent loss of chromosome 10 and 13q was observed, with minimal recurrent regions in 10q21.3 (75%) and 13q14.2-q14.3 (75%). Recurrent high-level amplification of 17p13.1-p11.2 was detected in leiomyosarcomas. Expression profiling using cDNA microarrays revealed four candidate genes in this region with high expression (AURKB, SREBF1, MFAP4, and FLJ10847). Altered expression of AURKB and SREBF1 has been observed previously in other malignancies. Hierarchical clustering of all samples separated GISTs and leiomyosarcomas into two distinct clusters. Statistical analysis identified six chromosomal regions, 1p36.11-p13.1, 9q21.11-9q34.3, 14q11.2-q23.2, 14q31.3-q32.33, 15q24.3-q26.3, and 22q11.21-q13.31, which were significantly different in copy number between GISTs and leiomyosarcomas. Our results show the potential of using array comparative genomic hybridization to classify histologically similar tumors such as GISTs and leiomyosarcomas. (Cancer Res 2006;66(18):8984-93)
Rare Germ Line CHEK2 Variants Identified in Breast Cancer Families Encode Proteins That Show Impaired Activation
Authors: Sodha Nayanta , Mantoni Tine S. , Tavtigian Sean V. , Eeles Rosalind , Garrett Michelle D. 
Published: September 2006

Abstract
Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutations indicate that two of these, delE161 (483-485delAGA) and R117G, are likely to be deleterious. We show that the proteins encoded by 1100delC and delE161 are both unstable and inefficiently phosphorylated at Thr68 in response to DNA damage, a step necessary for the oligomerization of Chk2. Oligomerization is in turn necessary for additional phosphorylation and full activation of the protein. A second rare mutation, R117G, is phosphorylated at Thr68 but fails to show a mobility shift on DNA damage, suggesting that it fails to become further phosphorylated and hence fully activated. Our results indicate that delE161 and R117G encode nonfunctional proteins and are therefore likely to be pathogenic. The findings from the biochemical analysis correlate well with predictions made by bioinformatics analysis. In addition, the results imply that these mutations, as well as 1100delC, cannot act in a dominant-negative manner to cause cancer, and tumorigenesis in association with these mutations may be due to haploinsufficiency. (Cancer Res 2006; 66(18): 8966-70)
Implications of Gene-Environment Interaction in Studies of Gene Variants in Breast Cancer: An Example of Dietary Isoflavones and the D356N Polymorphism in the Sex Hormone-Binding Globulin Gene
Authors: Low Yen-Ling , Dunning Alison M. , Dowsett Mitch , Luben Robert N. , Khaw Kay-Tee , Wareham Nick J. , Bingham Sheila A. 
Published: September 2006

Abstract
Studies to identify common genetic variants contributing to breast cancer risk often yield inconsistent results. Breast cancer is a complex disease involving both genetic and environmental determinants. Dietary isoflavones are thought to reduce breast cancer risk by stimulating circulating sex hormone-binding globulin (SHBG) levels. The SHBG gene contains a D356N polymorphism and the N variant is associated with reduced SHBG clearance compared with the D variant. In this study, we show a significant gene-environment interaction between SHBG D356N polymorphism and dietary isoflavone exposure on circulating SHBG levels in 1,988 postmenopausal women. SHBG levels were positively associated with isoflavones in women carrying the N variant (ηp2 = 1.9%; P = 0.006) but not in women carrying only the D variant (ηp2 = 0.0%; P = 0.999; Pinteraction = 0.019). This finding shows that the subtle effects of some genetic variants may be magnified and only become detectable in the presence of certain exposures. This gene-environment interaction might explain heterogeneity in studies associating SHBG gene variants and soy consumption with breast cancer risk in Far East population exposed to high isoflavone levels compared with populations with lower levels. (Cancer Res 2006; 66(18): 8980-3)
Small Molecules, Big Players: the National Cancer Institute's Initiative for Chemical Genetics
Authors: Tolliday Nicola , Clemons Paul A. , Ferraiolo Paul , Koehler Angela N. , Lewis Timothy A. , Li Xiaohua , Schreiber Stuart L. , Gerhard Daniela S. , Eliasof Scott 
Published: September 2006

Abstract
In 2002, the National Cancer Institute created the Initiative for Chemical Genetics (ICG), to enable public research using small molecules to accelerate the discovery of cancer-relevant small-molecule probes. The ICG is a public-access research facility consisting of a tightly integrated team of synthetic and analytical chemists, assay developers, high-throughput screening and automation engineers, computational scientists, and software developers. The ICG seeks to facilitate the cross-fertilization of synthetic chemistry and cancer biology by creating a research environment in which new scientific collaborations are possible. To date, the ICG has interacted with 76 biology laboratories from 39 institutions and more than a dozen organic synthetic chemistry laboratories around the country and in Canada. All chemistry and screening data are deposited into the ChemBank web site (http://chembank.broad.harvard.edu/) and are available to the entire research community within a year of generation. ChemBank is both a data repository and a data analysis environment, facilitating the exploration of chemical and biological information across many different assays and small molecules. This report outlines how the ICG functions, how researchers can take advantage of its screening, chemistry and informatic capabilities, and provides a brief summary of some of the many important research findings. (Cancer Res 2006; 66(18): 8935-42)