bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast Cancer Survival Is Associated with Telomere Length in Peripheral Blood Cells
Authors: Svenson Ulrika , Nordfjäll Katarina , Stegmayr Birgitta , Manjer Jonas , Nilsson Peter , Tavelin Björn , Henriksson Roger , Lenner Per , Roos Göran 
Published: May 2008

Abstract
Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P &lt; 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09–8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (≤median) showed an increased survival compared with N+ patients with long telomeres (P = 0.001). For patients with ages &lt;50 years with tumors &gt;16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33–6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease. [Cancer Res 2008;68(10):3618–23]
LKB1 and Lung Cancer: More Than the Usual Suspects
Authors: Shah Usman , Sharpless Norman E. , Hayes D. Neil 
Published: May 2008

Abstract
Often, the problem in cancer research is figuring out how a gene or pathway works in regulating cellular transformation. The question of what RAS activates or PTEN inhibits have been classic dilemmas of modern cancer biology. In these cases, biochemical and genetic studies have provided us with a fairly clear picture of the cancer relevant functions of these genes. For LKB1, a more recently identified human tumor suppressor gene, however, the problem is different. This serine-threonine kinase that is conserved from yeast to mammals seems to play a role in many diverse cellular pathways. Therefore, although elegant functional and genetic approaches have established critical roles for LKB1 in the regulation of metabolism, motility, polarity, and the cell cycle, the role(s) responsible for its true tumor suppressor function(s) is unknown. One is reminded of an Agatha Christie murder mystery where nearly every character in the book has reason to be suspected of committing the crime—there are too many suspects for how LKB1 might repress lung cancer. [Cancer Res 2008;68(10):3562–5]
Association of γ-Glutamyltransferase and Risk of Cancer Incidence in Men: A Prospective Study
Authors: Strasak Alexander M. , Rapp Kilian , Brant Larry J. , Hilbe Wolfgang , Gregory Martin , Oberaigner Willi , Ruttmann Elfriede , Concin Hans , Diem Günter , Pfeiffer Karl P. , Ulmer Hanno ,   and the VHM&PP Study Group
Published: May 2008

Abstract
Although several epidemiologic studies have shown that γ-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase &lt; 0.0001; P for trend &lt; 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P &lt; 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P &lt; 0.001), revealing markedly stronger associations in participants ages ≤65 years. Our findings, for the first time, show that elevated GGT is significantly associated with increased cancer risk in men. [Cancer Res 2008;68(10):3970–7]
The Nuclear Receptor Coactivator Amplified in Breast Cancer-1 Is Required for Neu (ErbB2/HER2) Activation, Signaling, and Mammary Tumorigenesis in Mice
Authors: Fereshteh Mark P. , Tilli Maddalena T. , Kim Sung Eun , Xu Jianming , O'Malley Bert W. , Wellstein Anton , Furth Priscilla A. , Riegel Anna T. 
Published: May 2008

Abstract
Overexpression of the oncogene amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) induces mammary tumorigenesis in mice. In breast cancer, high levels of AIB1/SRC-3 and the growth factor receptor HER2/neu predict resistance to endocrine therapy and poor outcome. However, a mechanistic relationship between AIB1/SRC-3 and HER2/neu in the development of breast cancer has not been shown. Here, we show that deletion of one allele of SRC-3 significantly delays Neu-induced mammary tumor development in mice. Homozygous deletion of SRC-3 in mice completely prevents Neu-induced tumor formation. By ages 3 to 4 months, Neu/SRC-3+/− mice exhibit a noticeable reduction in lateral side-bud formation, accompanied by reduced cellular levels of phosphorylated Neu compared with Neu/SRC-3wt mice. In Neu-induced tumors, high levels of SRC-3, phosphorylated Neu, cyclin D1, cyclin E, and proliferating cell nuclear antigen expression are observed, accompanied by activation of the AKT and c-Jun NH2 kinase (JNK) signaling pathways. In comparison, phosphorylated Neu, cyclin D1, and cyclin E are significantly decreased in Neu/SRC-3+/− tumors, proliferation is reduced, and AKT and JNK activation is barely detectable. Our data indicate that AIB1/SRC-3 is required for HER2/neu oncogenic activity and for the phosphorylation and activation of the HER2/neu receptor. We predict that reducing AIB1/SRC-3 levels or activity in the mammary epithelium could potentiate therapies aimed at inhibiting HER2/neu signaling in breast cancer. [Cancer Res 2008;68(10):3697–706]
Genetic Ablation of M3 Muscarinic Receptors Attenuates Murine Colon Epithelial Cell Proliferation and Neoplasia
Authors: Raufman Jean-Pierre , Samimi Roxana , Shah Nirish , Khurana Sandeep , Shant Jasleen , Drachenberg Cinthia , Xie Guofeng , Wess Jürgen , Cheng Kunrong 
Published: May 2008

Abstract
Colon epithelial cells express and most colon cancers overexpress M3 muscarinic receptors (M3R). In human colon cancer cells, post-M3R signaling stimulates proliferation. To explore the importance of M3R expression in vivo, we used the azoxymethane-induced colon neoplasia model. Mice treated with weekly i.p. injection of saline [10 wild-type (WT) mice] or azoxymethane (22 WT and 16 M3R−/− mice) for 6 weeks were euthanized at 20 weeks. At week 20, azoxymethane-treated WT mice weighed ∼16% more than M3R−/− mice (33.4 grams ± 1.0 grams versus 27.9 grams ± 0.5 grams; mean ± SE, P &lt; 0.001). In azoxymethane-treated M3R−/− mice, cell proliferation (BrdUrd staining) was reduced 43% compared with azoxymethane-treated WT mice (P &lt; 0.05). Whereas control mice (both WT and M3R−/−) had no colon tumors, azoxymethane-treated WT mice had 5.3 ± 0.5 tumors per animal. Strikingly, azoxymethane-treated M3R−/− mice had only 3.2 ± 0.3 tumors per mouse (P &lt; 0.05), a 40% reduction. Tumor volume in azoxymethane-treated M3R−/− mice was reduced 60% compared with azoxymethane-treated WT mice (8.1 mm3 ± 1.5 mm3 versus 20.3 mm3 ± 4.1 mm3; P &lt; 0.05). Compared with WT, fewer M3R−/− mice had adenomas (6% versus 36%; P = 0.05), and M3R−/− mice had fewer adenocarcinomas per mouse (0.6 ± 0.1 versus 1.7 ± 0.4; P &lt; 0.05). Eleven of 22 WT but no M3R−/− mice had multiple adenocarcinomas (P &lt; 0.001). Compared with WT, azoxymethane-treated M3R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M3R and post-M3R signaling are novel therapeutic targets for colon cancer. [Cancer Res 2008;68(10):3573–8]
Ikaros Modulates Cholesterol Uptake: A Link between Tumor Suppression and Differentiation
Authors: Loeper Siobhan , Asa Sylvia L. , Ezzat Shereen 
Published: May 2008

AbstractIkaros is a transcription factor that directs lymphoid lineage commitment and pituitary neuroendocrine cell expansion and function. Here, we show that Ikaros regulates the low-density lipoprotein receptor (LDL-R) to alter metabolism in pituitary corticotroph cells. The DNA-binding Ikaros isoform Ik1 binds and enhances activity of the LDL-R promoter. Ik1 decreases methylation and increases acetylation of histone H3 (Lys9) at the LDL-R promoter. Confocal microscopy and quantitative fluorometry show enhanced LDL endocytosis in Ik1-transfected cells that exhibit abundant endoplasmic reticulum, large Golgi complexes, and prominent secretory granule formation, consistent with more robust cholesterol incorporation into functionally relevant membrane-rich organelles. Consistent with these data, LDL-R−/− mice, like Ik−/− mice, have decreased circulating levels of adrenocorticotropic hormone. These findings expand the repertoire of Ikaros actions to include regulation of the cholesterol uptake metabolic pathway with therapeutic implications for lipid-modifying drugs in Ikaros-associated cancers. [Cancer Res 2008;68(10):3715–23]
Secretable Chaperone Grp170 Enhances Therapeutic Activity of a Novel Tumor Suppressor, mda-7/IL-24
Authors: Gao Ping , Sun Xiaolei , Chen Xing , Wang Yanping , Foster Barbara A. , Subjeck John , Fisher Paul B. , Wang Xiang-Yang 
Published: May 2008

Abstract
Melanoma differentiation–associated gene-7 (mda-7)/interleukin-24 (IL-24) is a cancer-specific, apoptosis-inducing gene with broad-spectrum antitumor activity, making it an ideal candidate for a novel cancer gene therapy. A systemic and sustained antitumor immune response generated at the time of initial molecular-targeted therapy would provide additional clinical benefits in cancer patients, resulting in improved prevention of tumor recurrence. In this study, we explored the therapeutic efficacy of intratumoral delivery of a nonreplicating adenoviral vector encoding mda-7/IL-24 (Ad.mda-7) and a secretable form of endoplasmic reticulum resident chaperone grp170 (Ad.sgrp170), a potent immunostimulatory adjuvant and antigen carrier. Intratumoral administration of Ad.mda-7 in combination with Ad.sgrp170 was more effective in controlling growth of TRAMP-C2 prostate tumor compared with either Ad.mda-7 or Ad.sgrp170 treatment. Generation of systemic antitumor immunity was shown by enhanced protection against subsequent tumor challenge and improved control of distant tumors. The combined treatments enhanced antigen and tumor-specific T-cell response, as indicated by increased IFN-γ production and cytolytic activity. Antibody depletion suggests that CD8+ T cells may be involved in the antitumor effect of the dual molecule–targeted therapies. Therefore, introducing immunostimulatory chaperone grp170 in situ strongly promotes the “immunogenic” cell death when delivered to the mda-7/IL-24–induced apoptotic tumor cells, indicating that an improved anticancer efficacy may be achieved by concurrently targeting both tumor and immune compartments. Given multiple undefined antigens present endogenously within prostate cancer, these data provide a rationale for combining sgrp170-based vaccine strategy with mda-7/IL-24–targeted cancer therapy to induce durable systemic immunity. [Cancer Res 2008;68(10):3890–8]
Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17
Authors: Nam Jeong-Seok , Terabe Masaki , Kang Mi-Jin , Chae Helen , Voong Nga , Yang Yu-an , Laurence Arian , Michalowska Aleksandra , Mamura Mizuko , Lonning Scott , Berzofsky Jay A. , Wakefield Lalage M. 
Published: May 2008

AbstractOverexpression of the immunosuppressive cytokine transforming growth factor β (TGF-β) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-β. We showed that CD8+ splenocytes from tumor-bearing mice expressed elevated interleukin (IL)-17 when compared with naive mice, and that CD8+ T cells could be induced to make IL-17 on addition of TGF-β and IL-6 in vitro. Treatment of mice with anti–TGF-β antibodies in vivo reduced IL-17 expression both in the tumor and the locoregional lymph nodes. Although IL-17 has not previously been shown to act as a survival factor for epithelial cells, we found that IL-17 suppressed apoptosis of several tumor cell lines in vitro, suggesting that this altered T-cell polarization has the potential to promote tumorigenesis directly, rather than indirectly through inflammatory sequelae. Consistent with this hypothesis, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-β may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17–dependent mechanism. [Cancer Res 2008;68(10):3915–23]
Urinary Metalloproteinases: Noninvasive Biomarkers for Breast Cancer Risk Assessment
Authors: Pories Susan E. , Zurakowski David , Roy Roopali , Lamb Carolyn C. , Raza Sughra , Exarhopoulos Alexis , Scheib Rochelle G. , Schumer Susan , Lenahan Corrine , Borges Virginia , Louis Gwendolyn W. , Anand Ankur , Isakovich Nina , Hirshfield-Bartek Judi , Wewer Ulla , Lotz Margaret M. , Moses Marsha A. 
Published: May 2008

Abstract
Matrix metalloproteinases (MMP) and a disintegrin and metalloprotease 12 (ADAM 12) can be detected in the urine of breast cancer patients and provide independent prediction of disease status. To evaluate the potential of urinary metalloproteinases as biomarkers to predict breast cancer risk status, urine samples from women with known risk marker lesions, atypical hyperplasia and lobular carcinoma in situ (LCIS), were analyzed. Urine samples were obtained from 148 women: 44 women with atypical hyperplasia, 24 women with LCIS, and 80 healthy controls. MMP analysis was done using gelatin zymography and ADAM 12 analysis was done via immunoblotting with monospecific antibodies and subsequent densitometric measurement. Positive urinary MMP-9 levels indicated a 5-fold risk of atypical hyperplasia and &gt;13-fold risk of LCIS compared with normal controls. Urinary ADAM 12 levels were significantly elevated in women with atypical hyperplasia and LCIS from normal controls, with receiver operating characteristic curve analysis showing an area under the curve of 0.914 and 0.950, respectively. To assess clinical applicability, a predictive index was developed using ADAM 12 in conjunction with Gail risk scores for women with atypia. Scores above 2.8 on this ADAM 12-Gail risk prediction index score are predictive of atypical hyperplasia (sensitivity, 0.976; specificity, 0.977). Our data suggest that the noninvasive detection and analysis of urinary ADAM 12 and MMP-9 provide important clinical information for use as biomarkers in the identification of women at increased risk of developing breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1034–12)
Estrogen Receptor–Negative Breast Cancer Is Less Likely to Arise among Lipophilic Statin Users
Authors: Kumar Anjali S. , Benz Christopher C. , Shim Veronica , Minami Christina A. , Moore Dan H. , Esserman Laura J. 
Published: May 2008

Abstract
Background: Preclinical studies have shown the anticancer potential of HMG-CoA reductase enzyme inhibitors (statins), whereas epidemiologic studies remain controversial. Because lipophilic statins show preclinical anticancer activity against hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)]–negative breast cancer models, we explored the hormone receptor phenotype of breast cancers that arise in statin users.
Methods: We did a retrospective cohort analysis via electronic pharmacy records from the Kaiser Permanente Northern California Cancer Registry on 2,141 female patients listed in 2003 as incident cases of breast malignancy. Measures included tumor grade, stage, and receptor phenotype in statin users versus nonusers and controlled for hormone replacement therapy and race.
Results: 387 of the 2,141 breast cancer patients used lipophilic statins [lovastatin (85%), simvastatin, and atorvastatin]. Fifty-one women developed ER/PR-negative tumors. The age-adjusted odds ratio (OR) of developing an ER/PR negative tumor was 0.63 (95% confidence interval, 0.43-0.92; P = 0.02) for statin use ≥1 year before breast cancer diagnosis compared with statin use &lt;1 year (including nonuse). Breast cancers in patients with ≥1 year of statin use were more likely to be low grade (OR, 1.44) and less invasive stage (OR, 1.42).
Conclusions: Breast cancer patients with exposure to statins have proportionately fewer ER/PR-negative tumors that are of lower grade and stage. Although our data set cannot address whether statins affect the incidence of breast cancer, we show that statin use may influence the phenotype of tumors. This suggests a new potential strategy for breast cancer prevention, that of combining statins with agents that prevent ER-positive cancer (tamoxifen, aromatase inhibitors). (Cancer Epidemiol Biomarkers Prev 2008;17(5):1028–33)
Direct Genotyping of Single Nucleotide Polymorphisms in Methyl Metabolism Genes Using Probe-Free High-Resolution Melting Analysis
Authors: Kristensen Lasse S. , Dobrovic Alexander 
Published: May 2008

Abstract
High-resolution melting (HRM) shows great promise for high-throughput, rapid genotyping of individual polymorphic loci. We have developed HRM assays for genotyping single nucleotide polymorphisms (SNP) in several key genes that are involved in methyl metabolism and may directly or indirectly affect the methylation status of the DNA. The SNPs are in the 5,10-methylenetetrahydrofolate reductase (MTHFR; C677T and A1298C), methionine synthetase (MTR; 5-methyltetrahydrofolate-homocysteine methyltransferase; A2756G), and DNA methyltransferase 3b (DNMT3b; C46359T and C31721T) loci. The choice of short amplicons led to greater melting temperature (Tm) differences between the two homozygous genotypes, which allowed accurate genotyping without the use of probes or spiking with control DNA. In the case of MTHFR, there is a second rarer SNP (rs4846051) close to the A1298C SNP that may result in inaccurate genotyping. We masked this second SNP by placing the primer over it and choosing a base at the polymorphic position that was equally mismatched to both alleles. The HRM assays were done on HRM capable real-time PCR machines rather than stand-alone HRM machines. Monitoring the amplification allows ready identification of samples that may give rise to aberrant melting curves because of PCR abnormalities. We show that samples amplifying markedly late can give rise to shifted melting curves without alteration of shapes and potentially lead to misclassification of genotypes. In conclusion, rapid and high-throughput SNP analysis can be done with probe-free HRM if sufficient attention is paid to amplicon design and quality control to omit aberrantly amplifying samples. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1240–7)
Association between Transillumination Breast Spectroscopy and Quantitative Mammographic Features of the Breast
Authors: Blackmore Kristina M. , Knight Julia A. , Lilge Lothar 
Published: May 2008

AbstractTransillumination breast spectroscopy (TiBS) uses nonionizing optical radiation to gain information about tissue properties directly from the breast. TiBS measurements were obtained from 225 women with normal mammograms. Principal component analysis was used to reduce the spectral data set into four principal components and to generate four TiBS scores (t1-t4) for each woman. These components and scores represent light scattering, water, lipid, and hemoglobin content. Percent density, dense area, and nondense area were measured using Cumulus. The association between TiBS scores and quantitative mammographic features was analyzed using linear regression stratified by menopausal status and adjusted for body mass index. Among premenopausal women, t1 and t3 were significantly associated with percent density (βt1 = −0.14, P = 0.04; βt3 = −2.43, P &lt; 0.0001), whereas t2 and t3 were significantly associated with dense area (βt2 = −1.57, P &lt; 0.0001; βt3 = −2.54, P &lt; 0.0001). Among postmenopausal women, t1, t3, and t4 were significantly associated with percent density (βt1 = −0.30, P &lt; 0.0001; βt3 = −2.51, P &lt; 0.0001; βt4 = 4.75, P &lt; 0.0001) and dense area (βt1 = −0.19, P = 0.004; βt3 = −2.13, P = 0.002; βt4 = 5.02, P &lt; 0.0001). Scores t2 and t4 were also significantly correlated with age among postmenopausal women (rt2 = 0.41 and rt4 = −0.36). Given the association with quantitative mammographic features and tissue changes related to age and menopause, TiBS scores may prove useful as intermediate markers in studies of breast cancer etiology and prevention. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1043–50)
Aberrant Crypt Focus Size Predicts Distal Polyp Histopathology
Authors: Kim Jae , Ng Jennie , Arozulllah Ahsan , Ewing Ronald , Llor Xavier , Carroll Robert E. , Benya Richard V. 
Published: May 2008

AbstractAberrant crypt foci (ACF) are the earliest histopathologic lesion associated with colorectal cancer. ACFs are commonly used as a surrogate marker for colorectal cancer chemoprevention studies in rodents and, more recently, in humans. However, ACF prevalence in unselected populations is not known, nor which ACF features are important for predicting polyp histopathology. To address these questions, we did magnification chromo-colonoscopy on all patients undergoing routine colorectal cancer screening over a 31-month period. ACFs were classified by location, size (small, &lt;20 crypts/ACF; medium, 20-100 crypts/ACF; large, &gt;100 crypts/ACF), and whether they were elevated above the tissue plane. Overall, 802 magnification chromo-colonoscopies with ACF enumeration were done. Mean patient age was 58.6 ± 8.5 years, of whom 56% were female, 58% were African American, 21% were Caucasian, and 16% were Latino. Total ACF number, along with increasing ACF size and elevation, correlated with the presence of distal hyperplastic polyps and were higher in African Americans. In contrast, ever-smaller ACFs correlated with the presence of distal adenomas and were independent of age and race. The odds ratio for patients with ≥6 small ACFs and adenomas was 6.02 (95% confidence interval, 2.64-13.70) compared with patients with ≤5 small ACFs, whereas the odds ratio for patients with ≥1 large ACF and hyperplastic polyps was 5.88 (95% confidence interval, 3.00-11.67) compared with patients with none. Small flat ACFs correlate with the presence of distal adenomas, whereas large raised ACFs correlate with the presence of hyperplastic polyps. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1155–62)