bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet-Derived Growth Factor-AA Is an Essential and Autocrine Regulator of Vascular Endothelial Growth Factor Expression in Non–Small Cell Lung Carcinomas
Authors: Shikada Yasunori , Yonemitsu Yoshikazu , Koga Takaomi , Onimaru Mitsuho , Nakano Toshiaki , Okano Shinji , Sata Shihoko , Nakagawa Kazunori , Yoshino Ichiro , Maehara Yoshihiko , Sueishi Katsuo
Published: September 2005

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non–small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA–dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.
Deficiency of Protein Kinase Cα in Mice Results in Impairment of Epidermal Hyperplasia and Enhancement of Tumor Formation in Two-Stage Skin Carcinogenesis
Authors: Hara Takeshi , Saito Yuriko , Hirai Takaaki , Nakamura Kenji , Nakao Kazuki , Katsuki Motoya , Chida Kazuhiro
Published: September 2005

We generated a mouse strain lacking protein kinase Cα (PKCα) and evaluated the significance of the enzyme in epithelial hyperplasia and tumor formation. PKCα-deficient mice exhibited increased susceptibility to tumor formation in two-stage skin carcinogenesis by single application of 7,12-dimethylbenz(a)anthracene (DMBA) for tumor initiation and repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion. Tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKCα suppresses tumor promotion. However, the severity of epidermal hyperplasia induced by topical TPA treatment was markedly reduced. In mutant mice, the number of 5-bromo-2′-deoxyuridine–labeled epidermal basal keratinocytes increased 16 to 24 hours after topical TPA treatment as in the case of wild-type mice, but significantly decreased at 36 and 48 hours. Furthermore, the regenerating epithelium induced by skin wound significantly decreased in thickness but was not structurally impaired. The enhanced tumor formation may not be associated with epidermal hyperplasia. The induction levels of epidermal growth factor (EGF) receptor ligands, tumor growth factor α (TGF-α), and heparin-binding EGF-like growth factor, in the skin of mutant mice by TPA treatment were significantly lower than those in the skin of wild-type mice. PKCα may regulate the supply of these EGF receptor ligands in basal keratinocytes, resulting in a reduced epidermal hyperplasia severity in the mutant mice. We propose that PKCα positively regulates epidermal hyperplasia but negatively regulates tumor formation in two-stage skin carcinogenesis.
A Haplotype-Based Case-Control Study of BRCA1 and Sporadic Breast Cancer Risk
Authors: Freedman Matthew L. , Penney Kathryn L. , Stram Daniel O. , Riley Stephanie , McKean-Cowdin Roberta , Le Marchand Loïc , Altshuler David , Haiman Christopher A.
Published: September 2005

Rare, highly penetrant germ line mutations in BRCA1 strongly predispose women to a familial form of breast and ovarian cancer. Whether common variants (either coding or noncoding) at this locus contribute to the more common form of the disease is not yet known. We tested common variation across the BRCA1 locus in African American, Native Hawaiian, Japanese, Latino, and White women in the Multiethnic Cohort Study. Specifically, 28 single nucleotide polymorphisms (SNPs) spanning the BRCA1 gene were used to define patterns of common variation in these populations. The majority of SNPs were in strong linkage disequilibrium with one another, indicating that our survey captured most of the common inherited variation across this gene. Nine tagging SNPs, including five missense SNPs, were selected to predict the common BRCA1 variants and haplotypes among the non–African American groups (five additional SNPs were required for African Americans) and genotyped in a breast cancer case-control study nested in the Multiethnic Cohort Study (cases, n = 1,715; controls, n = 2,502). We found no evidence for significant associations between common variation in BRCA1 and risk of breast cancer. Given the large size of our study population and detailed analysis of the locus, this result indicates either that common variants in BRCA1 do not substantially influence sporadic breast cancer risk, or that unmeasured heterogeneity in the breast cancer phenotype or unmeasured interactions with genetic or environmental exposures obscure our ability to detect any influence that may be present.
Epigenetic Inactivation of SFRP Genes and TP53 Alteration Act Jointly as Markers of Invasive Bladder Cancer
Authors: Marsit Carmen J. , Karagas Margaret R. , Andrew Angeline , Liu Mei , Danaee Hadi , Schned Alan R. , Nelson Heather H. , Kelsey Karl T.
Published: September 2005

In the United States each year, almost 13,000 deaths are attributable to bladder cancer, with the majority of these deaths related to higher stage, muscle-invasive solid tumors. Epigenetic silencing of the secreted frizzled receptor proteins (SFRP), antagonists of the WNT pathway, leads to constitutive WNT signaling, altering cell morphology and motility. Identifying alterations in this pathway in bladder cancer may prove useful for defining the invasive phenotype and provide targets for guiding therapy. Using a population-based study of bladder cancer (n = 355), we examined epigenetic alterations, specifically gene promoter hypermethylation, of four SFRP genes in addition to immunohistochemical staining of TP53, which has been previously shown to be a predictor of invasive disease. We observed a significant linear trend (P < 0.0004) in the magnitude of the risk of invasive disease with the number of SFRP genes methylated. Both TP53 alteration and SFRP gene methylation showed significant independent associations with invasive bladder cancer. Strikingly, in examining the joint effect of these alterations, we observed a >30-fold risk of invasive disease for patients with both altered SFRP gene methylation and intense TP53 staining (odds ratio, 32.1; P < 10−13). Overall patient survival was significantly poorer in patients with any SFRP genes methylated (P < 0.0003) and in proportional hazards modeling, patients with methylation of any SFRP gene had significantly poorer overall survival (hazard ratio, 1.78; P < 0.02) controlled for TP53 staining intensity and other survival-associated factors. Classifying tumors based on SFRP methylation status and TP53 protein staining intensity may be a clinically powerful predictor of invasive, deadly disease.
Genetic Heterogeneity of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Cell Lines Revealed by a Rapid and Sensitive Detection System, the Peptide Nucleic Acid-Locked Nucleic Acid PCR Clamp
Authors: Nagai Yoshiaki , Miyazawa Hitoshi , Huqun  , Tanaka Tomoaki , Udagawa Kiyoshi , Kato Motoyasu , Fukuyama Shunichiro , Yokote Akemi , Kobayashi Kunihiko , Kanazawa Minoru , Hagiwara Koichi
Published: September 2005

Lung cancer is one of the leading causes of the cancer death worldwide. Gefitinib is an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and has been introduced in the treatment of advanced lung cancers. The responsiveness to gefitinib has been linked to the presence of EGFR mutations. Clinical samples contain many normal cells in addition to cancer cells. A method capable of detecting EGFR mutations in a large background of wild-type EGFR genes could provide a superior clinical test. We developed a rapid and sensitive detection system for EGFR mutations named the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp that can detect EGFR mutations in the presence of 100-to 1,000-fold background of wild-type EGFR. We used this method to screen 30 non–small cell lung cancer cell lines established from Japanese patients. In addition to 11 cell lines that have mutations, we found 12 cell lines in which specific mutations are observed only in the subpopulation(s) of the cells. Genetic heterogeneity of EGFR suggests that the EGFR gene is unstable in established cancers and the heterogeneity may explain variable clinical responses of lung cancers to gefitinib.
Protein Kinase C-ε Regulates the Apoptosis and Survival of Glioma Cells
Authors: Okhrimenko Hana , Lu Wei , Xiang Cunli , Hamburger Nathan , Kazimirsky Gila , Brodie Chaya
Published: September 2005

In this study, we examined the role of protein kinase C (PKC)-ε in the apoptosis and survival of glioma cells using tumor necrosis factor–related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKCε expression. Treatment of glioma cells with TRAIL induced activation, caspase-dependent cleavage, and down-regulation of PKCε within 3 to 5 hours of treatment. Overexpression of PKCε inhibited the apoptosis induced by TRAIL, acting downstream of caspase 8 and upstream of Bid cleavage and cytochrome c release from the mitochondria. A caspase-resistant PKCε mutant (D383A) was more protective than PKCε, suggesting that both the cleavage of PKCε and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKCε in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKCε and found that silencing of PKCε expression induced apoptosis of various glioma cell lines and primary glioma cultures. To delineate the molecular mechanisms involved in the apoptosis induced by silencing of PKCε, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKCε did not affect the expression of Bcl2 and Bax or the phosphorylation and expression of Erk1/2, c-Jun-NH2-kinase, p38, or STAT, whereas it selectively reduced the expression of AKT. Similarly, TRAIL reduced the expression of AKT in glioma cells and this decrease was abolished in cells overexpressing PKCε. Our results suggest that the cleavage of PKCε and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKCε regulates AKT expression and is essential for the survival of glioma cells.
Mechanistic Analysis of the Role of BLCA-4 in Bladder Cancer Pathobiology
Authors: Myers-Irvin Julie M. , Van Le Thu-Suong , Getzenberg Robert H.
Published: September 2005

Analysis of alterations in nuclear structure associated with bladder cancer has revealed specific changes associated with the disease. This includes the identification of six bladder cancer-specific proteins and the successful development of urine-based immunoassays for the detection of two of these biomarkers, BLCA-1 and BLCA-4. The purpose of this study is to examine the functional aspects of BLCA-4 and its potential role in bladder cancer pathobiology. Sequence analysis of BLCA-4 reveals that it is a member of the ETS transcription factor family and that it seems to associate with transcription factors. To examine the effects of this protein, the gene encoding BLCA-4 was stably transfected into human urothelial cells. BLCA-4 expression was confirmed by both PCR and Western blot analysis. BLCA-4 overexpressing clones exhibit a 4.3-fold greater proliferation rate than vector only controls or untransfected cells. Microarray analysis comparing gene expression patterns between overexpressing clones and vector only controls revealed that numerous genes were up-regulated in cells that overexpress BLCA-4. Up-regulated genes included interleukin-1α (IL-1α), IL-8, and thrombomodulin, and the protein expression of these genes was confirmed by immunoblots. This information has provided a potential model of BLCA-4 action. Overexpression of BLCA-4 seems to increase the growth rate in cells and also causes cells to express a more tumorigenic phenotype.
PACE4 Expression in Mouse Basal Keratinocytes Results in Basement Membrane Disruption and Acceleration of Tumor Progression
Authors: Bassi Daniel E. , Lopez De Cicco Ricardo , Cenna Jonathan , Litwin Samuel , Cukierman Edna , Klein-Szanto Andres J.P.
Published: September 2005

Collagen type IV degradation results in disruption and breakdown of the normal basement membrane architecture, a key process in the initiation of tumor microinvasion into the connective tissue. PACE4, a proprotein convertase, activates membrane type matrix metalloproteinases (MT-MMPs) that in turn process collagenase type IV. Because PACE4 is overexpressed in skin carcinomas and in vitro overexpression of PACE4 resulted in enhanced invasiveness, we investigated whether or not in vivo PACE4 expression leads to the acquisition of invasiveness and increased tumorigenesis. Two transgenic mouse lines were designed by targeting PACE4 to the epidermal basal keratinocytes. Transgenic keratinocytes showed increased processing of MT1-MMP and MT2-MMP resulting in collagenase IV activation and collagen type IV degradation. Higher collagenolytic activity partially disrupted normal basement membrane architecture favoring epithelial endophytic growth into the dermis and accelerating invasion and metastasis after chemical carcinogenesis. PACE4 overexpression resulted in enhanced susceptibility to carcinogenesis and tumor progression pointing to a new target for blocking tumor cell invasiveness.
Apoptin Nuclear Accumulation Is Modulated by a CRM1-Recognized Nuclear Export Signal that Is Active in Normal but not in Tumor Cells
Authors: Poon Ivan K.H. , Oro Cristina , Dias Manisha M. , Zhang Jingpu , Jans David A.
Published: September 2005

Tumor cell–specific activity of chicken anemia virus viral protein 3 (VP3 or apoptin) is believed to be dependent on its ability to localize in the nucleus of transformed but not of primary or nontransformed cells. The present study characterizes the signals responsible for the novel nucleocytoplasmic trafficking properties of VP3 using two isogenic tumor/nontumor cell pairs. In addition to the tumor cell–specific nuclear targeting signal, comprising two stretches of basic amino acids in the VP3 COOH terminus which are highly efficient in tumor but not in normal cells, we define the CRM1-recognized nuclear export sequence (NES) within the VP3 tumor cell–specific nuclear targeting signal for the first time. Intriguingly, the NES (amino acids 97-105) is functional in normal but not in tumor cells through the action of the threonine 108 phosphorylation site adjacent to the NES which inhibits its action. In addition, we characterize a leucine-rich sequence (amino acids 33-46) that assists VP3 nuclear accumulation by functioning as a nuclear retention sequence, conferring association with promyelocytic leukemia nuclear bodies. This unique combination of signals is the basis of the tumor cell–specific nuclear targeting abilities of VP3.
OLIG2 (BHLHB1), a bHLH Transcription Factor, Contributes to Leukemogenesis in Concert with LMO1
Authors: Lin Ying-Wei , Deveney Ramona , Barbara Mary , Iscove Norman N. , Nimer Stephen D. , Slape Christopher , Aplan Peter D.
Published: September 2005

OLIG2 (originally designated BHLHB1) encodes a transcription factor that contains the basic helix-loop-helix motif. Although expression of OLIG2 is normally restricted to neural tissues, overexpression of OLIG2 has been shown in patients with precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL). In the current study, we found that overexpression of OLIG2 was not only found in oligodendroglioma samples and normal neural tissue but also in a wide spectrum of malignant cell lines including leukemia, non–small cell lung carcinoma, melanoma, and breast cancer cell lines. To investigate whether enforced expression of OLIG2 is oncogenic, we generated transgenic mice that overexpressed OLIG2 in the thymus. Ectopic OLIG2 expression in the thymus was only weakly oncogenic as only 2 of 85 mice developed pre-T LBL. However, almost 60% of transgenic mice that overexpressed both OLIG2 and LMO1 developed pre-T LBL with large thymic tumor masses. Gene expression profiling of thymic tumors that developed in OLIG2/LMO1 mice revealed up-regulation of Notch1 as well as Deltex1 (Dtx1) and pre T-cell antigen receptor α (Ptcra), two genes that are considered to be downstream of Notch1. Of note, we found mutations in the Notch1 heterodimerization or proline-, glutamic acid-, serine-, and threonine-rich domain in three of six primary thymic tumors. In addition, growth of leukemic cell lines established from OLIG2/LMO1 transgenic mice was suppressed by a γ-secretase inhibitor, suggesting that Notch1 up-regulation is important for the proliferation of OLIG2-LMO1 leukemic cells.
MicroRNA Gene Expression Deregulation in Human Breast Cancer
Authors: Iorio Marilena V. , Ferracin Manuela , Liu Chang-Gong , Veronese Angelo , Spizzo Riccardo , Sabbioni Silvia , Magri Eros , Pedriali Massimo , Fabbri Muller , Campiglio Manuela , Ménard Sylvie , Palazzo Juan P. , Rosenberg Anne , Musiani Piero , Volinia Stefano , Nenci Italo , Calin George A. , Querzoli Patrizia , Negrini Massimo , Croce Carlo M.
Published: September 2005

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.
Gene Expression of Angiogenic Factors Correlates with Metastatic Potential of Prostate Cancer Cells
Authors: Aalinkeel Ravikumar , Nair Madhavan P. N. , Sufrin Gerald , Mahajan Supriya D. , Chadha Kailash C. , Chawda Ram P. , Schwartz Stanley A.
Published: September 2005

We hypothesize that expression of proangiogenic genes correlates with the metastatic potential of prostate cancer cells. LNCaP, DU-145, and PC-3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as we demonstrated by their capacity to invade an extracellular matrix, an established tumor invasion assay. The constitutive gene expression of the proangiogenic factors, vascular endothelial growth factor, intercellular adhesion molecule-1, interleukin-8, and transforming growth factor-β2, was significantly greater in the more metastatic DU-145 and PC-3 cells as compared with LNCaP cells. Matrix metalloproteinase (MMP)-9 is thought to contribute to the invasive phenotype of tumor cells. PC-3 cells showed increased expression of MMP-9 and membrane type 4-MMP as compared with LNCaP and DU-145. Tissue inhibitors of metalloproteinase 1 and 4 gene expression were elevated in DU-145 and PC-3 cells, but paradoxically, LNCaP cells had undetectable levels of these genes. We transfected and overexpressed MMP-9 in poorly metastatic LNCaP cells and measured their invasive activity. Transient expression of human MMP-9 in LNCaP cells produced a 3–5-fold increase in MMP-9 activity with a comparable increase in invasiveness. Antisense ablation of the expression of MMP-9 in DU-145 and PC-3 cells produced concomitant inhibition of the gene expression of the proangiogenic factors, vascular endothelial growth factor, and intercellular adhesion molecule-1 (ICAM-1). Treatment of DU-145 and PC-3 cells with a selective chemical inhibitor of MMP-9 proteinase activity also inhibited their invasive activity. These results support our hypothesis that metastatic potential of prostate cancer cells correlates with expression of proangiogenic factors.
HER-2/neu-Mediated Regulation of Components of the MHC Class I Antigen-Processing Pathway
Authors: Herrmann Felix , Lehr Hans-Anton , Drexler Ingo , Sutter Gerd , Hengstler Jan , Wollscheid Ursula , Seliger Barbara
Published: September 2005

Because of its amplification and/or overexpression in many human tumors, the HER-2/neu proto-oncogene represents an attractive target for T-cell-mediated vaccination strategies. However, overexpression of oncogenes is often associated with defective expression of components of the MHC class I antigen-processing machinery (APM), thereby resulting in an immune escape phenotype of oncogene-transformed cells. To determine whether HER-2/neu influences the MHC class I antigen-processing pathway, the expression pattern of different APM components was examined in murine in vitro models of constitutive and tetracycline-controlled HER-2/neu expression. In comparison with HER-2/neu− control cells, HER-2/neu+ fibroblasts exhibit reduced levels of MHC class I surface antigens that were associated with impaired expression and/or function of the peptide transporter associated with antigen processing, the proteasome subunits low molecular weight protein 2 and low molecular weight protein 10, the proteasome activators PA28α and PA28β, and tapasin. These APM abnormalities resulted in reduced sensitivity to lysis by CTLs. The HER-2/neu-mediated immune escape phenotype could be corrected by IFN-γ treatment. The clinical relevance of this finding was supported by an inverse correlation between HER-2/neu and the peptide transporter associated with antigen-processing protein expression as determined by immunhistochemical analysis of a series of HER-2/neu− and HER-2/neu+ breast cancer specimens. Thus, a functional link between deficient APM component expression and HER-2/neu overexpression is proposed that might influence the design of HER-2/neu-targeted T-cell-based immunotherapeutic strategies.
Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance
Authors: Yasui Kohichiroh , Mihara Saori , Zhao Chen , Okamoto Hiroyuki , Saito-Ohara Fumiko , Tomida Akihiro , Funato Tadao , Yokomizo Akira , Naito Seiji , Imoto Issei , Tsuruo Takashi , Inazawa Johji
Published: September 2005

Chemoresistance is a major obstacle for successful treatment of cancer. To identify regions of the genome associated with acquired resistance to therapeutic drugs, we conducted molecular cytogenetic analyses of 23 cancer-cell lines, each resistant to either camptothecin, cisplatin, etoposide (VP-16), Adriamycin, or 1-β-d-arabinofuranosylcytosine, although the parental tumor lines were not. Subtractive comparative genomic hybridization studies revealed regions of gain or loss in DNA-copy numbers that were characteristic of drug-resistant cell lines; i.e., differences from their drug-sensitive parental cell lines. Thirteen ATP-binding cassette (ABC) transporter genes [ABCA3, ABCB1 (MDR1), ABCB6, ABCB8, ABCB10, ABCB11, ABCC1 (MRP1), ABCC4, ABCC9, ABCD3, ABCD4, ABCE1, and ABCF2] were amplified among 19 of the resistant cell lines examined. Three genes encoding antiapoptotic BCL-2 proteins (BCL2L2, MCL1, and BCL2L10) were also amplified and consequently overexpressed in three of the derivative lines. Down-regulation of BCL2L2 with an antisense oligonucleotide sensitized a VP-16 resistant ovarian-cancer cell line (SKOV3/VP) to VP-16. A decrease in copy numbers of genes encoding deoxycytidine kinase, DNA topoisomerase I, and DNA topoisomerase II α reduced their expression levels in one cytosine arabinoside-resistant line, two of three camptothecin-resistant lines, and two of five VP-16-resistant cell lines, respectively. Our results indicated that changes in DNA-copy numbers of the genes mentioned can activate or down-regulate them in drug-resistant cell lines, and that such genomic alterations might be implicated in acquired chemoresistance.
Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells
Authors: Boulay Anne , Zumstein-Mecker Sabine , Stephan Christine , Beuvink Iwan , Zilbermann Frederic , Haller Roland , Tobler Sonja , Heusser Christoph , O’Reilly Terence , Stolz Barbara , Marti Andreas , Thomas George , Lane Heidi A.
Published: September 2005

The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23–30%, respectively], with 3–5 mg/kg RAD001 administered once weekly (T/C, 14–36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (≥72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (≥7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nm RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.
Plasma and Dietary Carotenoids, and the Risk of Prostate Cancer
Authors: Wu Kana , Erdman John W. , Schwartz Steven J. , Platz Elizabeth A. , Leitzmann Michael , Clinton Steven K. , DeGroff Valerie , Willett Walter C. , Giovannucci Edward
Published: September 2005

The association between plasma carotenoids and prostate cancer risk was investigated in a case-control study nested within the prospective Health Professionals Follow-up Study. We matched 450 incident prostate cancer cases diagnosed from 1993–1998 to 450 controls by age, time, month, and year of blood donation.

Modest inverse, but not statistically significant, associations were observed among plasma α-carotene, β-carotene, and lycopene concentrations, and overall risk of prostate cancer diagnosis {odds ratio (highest versus lowest quintile; OR), α-carotene: OR, 0.67 [95% confidence interval (CI), −0.40–1.09]; β-carotene: OR, 0.78 (95% CI, 0.48–1.25); lycopene: OR, 0.66 (95% CI, 0.38–1.13)}. The inverse association between plasma lycopene concentrations and prostate cancer risk was limited to participants who were 65 years or older (OR, 0.47; 95% CI, 0.23–0.98) and without a family history of prostate cancer (OR, 0.48; 95% CI, 0.26–0.89). Combining, older age and a negative family history provided similar results (OR, 0.43; 95% CI, 0.18–1.02). Inverse associations between β-carotene and prostate cancer risk were also found among younger participants (<65 years of age; OR, 0.36; 95% CI, 0.14–0.91; Ptrend = 0.03). Combining dietary intake and plasma data confirmed our results.

We found a statistically significant inverse association between higher plasma lycopene concentrations and lower risk of prostate cancer, which was restricted to older participants and those without a family history of prostate cancer. This observation suggests that tomato products may exhibit more potent protection against sporadic prostate cancer rather than those with a stronger familial or hereditary component. In addition, our findings also suggest that among younger men, diets rich in β-carotene may also play a protective role in prostate carcinogenesis.
Reported Use of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Was Not Associated with Reduced Recurrence of Colorectal Adenomas
Authors: Wei Jeffrey T. , Mott Leila A. , Baron John A. , Sandler Robert S. ,   for the Polyp Prevention Study Group
Published: September 2005

We did a secondary analysis of data from three large colorectal adenoma chemoprevention trials to assess the association between 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor use and reduced risk of recurrent colorectal adenomas. Reported use of HMG-CoA reductase inhibitors was not associated with a reduced recurrence of colorectal adenomas, multiple adenomas, or advanced adenomas. Lack of statistical power from limited exposure to HMG-CoA reductase inhibitors might be responsible for the lack of association.
Seroreactivity to Human Papillomavirus (HPV) Types 16, 18, or 31 and Risk of Subsequent HPV Infection
Authors: Viscidi Raphael P. , Schiffman Mark , Hildesheim Allan , Herrero Rolando , Castle Philip E. , Bratti Maria C. , Rodriguez Ana Cecilia , Sherman Mark E. , Wang Sophia , Clayman Barbara , Burk Robert D.
Published: September 2005

Whether antibodies to human papillomavirus (HPV) capsids, elicited by natural infection, are protective is unknown. This question was addressed in a population-based cohort of 7046 women in Costa Rica by examining the association between baseline seroreactivity to HPV-16, HPV-18, or HPV-31 virus-like particles and the risk of subsequent HPV infection at a follow-up visit 5–7 years after enrollment. Seropositivity to HPV-16, HPV-18, or HPV-31 was not associated with a statistically significant decreased risk of infection with the homologous HPV type [relative risk (RR) and [95% confidence interval (CI)], 0.74 (0.45–1.2), 1.5 (0.83–2.7), and 0.94 (0.48–1.8), respectively]. Seropositivity to HPV-16 or HPV-31 was not associated with a decreased risk of infection with HPV-16 or its genetically related types [RR (95% CI), 0.82 (0.61–1.1) and 0.93 (0.68–1.2), respectively]. Seropositivity to HPV-18 was not associated with a decreased risk of infection with HPV-18 or its genetically related types (RR 1.3; 95% CI 1.0–1.8). Thus, we did not observe immunity, although a protective effect from natural infection cannot be excluded because of the limits of available assays and study designs.
Peptic Ulcer Disease and the Risk of Bladder Cancer in a Prospective Study of Male Health Professionals
Authors: Michaud Dominique S. , Mysliwiec Pauline A. , Aldoori Walid , Willett Walter C. , Giovannucci Edward
Published: September 2005

Helicobacter pylori is a risk factor for gastric and duodenal ulcers, but gastric ulcers generally occur in individuals who have low acid production and diffuse gastritis, whereas duodenal ulcers are more likely to occur with high acid output and antrum-predominant gastritis. Low acid production, gastritis, and ulcer healing each contribute to poor antioxidant absorption, oxidative stress, and elevated nitrite levels in the stomach. N-Nitrosamines are known carcinogens, and nitrate ingestion has been related to bladder cancer risk. Consequently, we hypothesized that the gastric conditions associated with gastric ulcers may contribute to elevated bladder cancer risk. We thus examined the association between self-reported history of peptic ulcer disease and the risk of bladder cancer (414 cases) over 14 years of follow-up in the Health Professional Follow-Up Study. Cox proportional hazards models were performed to adjust for known risk factors of bladder cancer. Men who reported a gastric ulcer before 1986 had a significantly higher risk of bladder cancer compared with those with no history of gastric ulcer (relative risk = 1.55, 95% confidence interval = 1.03–2.33, controlling for smoking and other potential confounders). No association was observed for duodenal ulcers (multivariate relative risk = 0.97, 95% confidence interval = 0.68–1.38). The ulcers in this study were based solely on self-report and not medical records; consequently, misclassification of ulcers may have occurred. Although intriguing, these findings need to be replicated.
Increased Prevalence of theHFE C282YHemochromatosis Allele in Women with Breast Cancer
Authors: Kallianpur Asha R. , Hall Lynn D. , Yadav Meeta , Christman Brian W. , Dittus Robert S. , Haines Jonathan L. , Parl Fritz F. , Summar Marshall L.
Published: September 2005

Individuals with the major hemochromatosis (HFE) allele C282Y and iron overload develop hepatocellular and some extrahepatic malignancies at increased rates. No association has been previously reported between the C282Y allele and breast cancer. We hypothesized that due to the pro-oxidant properties of iron, altered iron metabolism in C282Y carriers may promote breast carcinogenesis. Because 1 in 10 Caucasians of Northern European ancestry carries this allele, any impact it may have on breast cancer burden is potentially great. We determined C282Y genotypes in 168 patients who underwent high-dose chemotherapy and blood cell transplantation for cancer: 41 with breast cancer and 127 with predominantly hematological cancers (transplant cohort). Demographic, clinical, and tumor characteristics were reviewed in breast cancer patients. The frequency of C282Y genotypes in breast cancers was compared with the frequency in nonbreast cancers, an outpatient sample from Tennessee (n = 169), and a published United States national sample. The frequency of at least one C282Y allele in breast cancers was higher (36.6%, 5 homozygotes/10 heterozygotes) than frequencies in Tennessee (12.7%, P < 0.001), the general population (12.4%, P < 0.001), and similarly selected nonbreast cancers (17.0%, P = 0.008). The likelihood of breast cancer in the transplant cohort increased with C282Y allele dose (Ptrend = 0.010). These results were supported by the finding in a nontransplant cohort of a higher frequency of C282Y mutations in Caucasian (18.4%, P = 0.039) and African-American (8.5%, P = 0.005) women with breast cancer than race-specific national frequency estimates. A high prevalence of C282Y alleles in women with breast cancer with and without poor risk features suggests that altered iron metabolism in C282Y carriers may promote the development of breast cancer and/or more aggressive forms of the disease.
MTHFR
Polymorphisms, Dietary Folate Intake, and Breast Cancer Risk
Authors: Shrubsole Martha J. , Gao Yu-Tang , Cai Qiuyin , Shu Xiao Ou , Dai Qi , Hébert James R. , Jin Fan , Zheng Wei
Published: September 2005

Folate plays an important role in DNA methylation, synthesis, and repair; intake has been associated with breast cancer. The folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR) is polymorphic at nucleotides 677 (C→T) and 1298 (A→C), resulting in allozymes with decreased activity. We evaluated these two common polymorphisms and their effects on the folate intake and breast cancer risk association in a population-based case-control study of 1144 breast cancer cases and 1236 controls using a PCR-RFLP-based assay. All subjects completed in-person interviews, which included a food frequency questionnaire. Unconditional logistic regression models were used to calculate odds ratios and their 95% confidence intervals, after adjusting for potential confounding factors. Cases and controls were similar in the distribution of MTHFR polymorphisms at codons 677 (41.4% cases and 41.8% controls carried the T allele) and 1298 (17.6% cases and 17.5% controls carried the C allele). An inverse association of breast cancer risk with folate intake was observed in all genotype groups, particularly among subjects with the 677TT genotype. Compared with those with the 677CC genotype and high folate, the adjusted odds ratios (95% confidence intervals) associated with low folate intake were 1.94 (1.15–3.26), 2.17 (1.34–3.51), and 2.51 (1.37–4.60) for subjects who had CC, CT, and TT genotypes (p for interaction, 0.05). No modifying effect of A1298C genotypes on the association of folate intake with breast cancer risk was observed. Results of this study suggest that the MTHFR C677T polymorphisms may modify the association between dietary folate intake and breast cancer risk.
Genetic Polymorphisms in
GSTM1
,
GSTP1
, and
GSTT1
and the Risk for Breast Cancer
Authors: Egan Kathleen M. , Cai Qiuyin , Shu Xiao-Ou , Jin Fan , Zhu Tian-Li , Dai Qi , Gao Yu-Tang , Zheng Wei
Published: September 2005

Purpose: We studied the relation of breast cancer to common deletion mutations in GSTM1 and GSTT1 and the functional Ile105Val polymorphism in GSTP1 in a large, population-based case-control study conducted in China and performed a meta-analysis to summarize the literature.

Experimental Design: In the case-control study, a total of 1144 breast cancer cases and 1221 community controls were genotyped for GSTM1, GSTP1, and GSTT1 using PCR-based methods. Associations of genotypes and breast cancer were evaluated in logistic regression models. Meta-analysis odds ratios (ORs) were estimated using a fixed effects model.

Results: In the case-control study, associations were null for GSTM1 [age-adjusted OR 0.97, 95% confidence interval (CI): 0.82–1.14] and GSTT1 (OR 0.97, 95% CI: 0.83–1.15). A significant increase in risk was observed among homozygotes for the variant Ile105Val polymorphism (OR 1.92, 95% CI: 1.21–3.04). No combined effects of GSTM1, GSTP1, and GSTT1 genotypes or interactions with potential effect modifiers were detected. All results were similar in pre- and postmenopausal women and for early versus advanced stage breast cancer. The meta-analysis, based predominately on Caucasian women, supported null results for the homozygous deletion variant in GSTM1 (summary OR 1.05; combining 19 studies) and GSTT1 (summary OR 1.11; 15 studies). Meta-analysis results for the homozygous GSTP1 variant indicated no overall association (summary OR 1.04; 10 studies), although results varied significantly across studies (P = 0.009).

Conclusions: This large case-control study provides strong support for earlier studies showing no overall association of the GSTM1 and GSTT1 deletion polymorphisms with breast cancer risk. The GSTP1 variant may be relevant to breast cancer risk in Asian populations.
Chlamydial Antibodies and Risk of Prostate Cancer
Authors: Anttila Tarja , Tenkanen Leena , Lumme Sonja , Leinonen Maija , Gislefoss Randi Elin , Hallmans Göran , Thoresen Steinar , Hakulinen Timo , Luostarinen Tapio , Stattin Pär , Saikku Pekka , Dillner Joakim , Lehtinen Matti , Hakama Matti
Published: September 2005

Objective: We assessed the risk of prostate cancer by exposure to Chlamydia trachomatis.

Method: Seven hundred thirty eight cases of prostate cancer and 2,271 matched controls were identified from three serum sample banks in Finland, Norway, and Sweden by linkage to the population based cancer registries.

Results: A statistically significant inverse association (odds ratio, 0.69; 95% confidence interval, 0.51-0.94) was found. It was consistent by different serotypes and there was a consistent dose-response relationship.

Conclusion: C. trachomatis infection is not likely to increase the risk of prostate cancer. Whether the inverse relationship is true or due to difficulties in measuring the true exposure in prostatic tissue by serology, confounders or other sources of error remain open.
Association of Gain and Loss of Weight before and after Menopause with Risk of Postmenopausal Breast Cancer in the Iowa Women's Health Study
Authors: Harvie Michelle , Howell Anthony , Vierkant Robert A. , Kumar Nagi , Cerhan James R. , Kelemen Linda E. , Folsom Aaron R. , Sellers Thomas A.
Published: September 2005

Obesity and adult weight gain are well-established risk factors for postmenopausal breast cancer. Although there are a few studies demonstrating the contribution of adult weight gain to breast cancer risk, whether weight gain during a critical time period is specifically associated with risk, or whether subsequent weight loss among women who have gained weight will reduce the excess risk, is not firmly established. We investigated the association of changes in weight (loss or gain in excess of 5% of body weight) using two risk factor models: (a) age 18 to 30 years and age 30 years to menopause and (b) age 30 years to menopause and after the menopause to the baseline study in 1986 on risk of postmenopausal breast cancer in a prospective cohort of 33,660 postmenopausal women in Iowa. Over 15 years of follow-up, 1,987 cases of breast cancer occurred. Data were analyzed using proportional hazards regression models adjusted for established breast cancer risk factors. The most frequently observed pattern of body weight over time was a consistent increase; these women were observed to have the highest rates of breast cancer and served as the reference category for all comparisons. The lowest-risk groups were (a) women who maintained or lost weight from age 18 to 30 years and then lost weight from age 30 years to menopause [risk ratio (RR), 0.36; 95% confidence interval (95% CI), 0.22-0.60] and (b) women who maintained or lost weight from age 30 years to menopause and then lost weight after the menopause (RR, 0.48; 95% CI, 0.22-0.65). Women who gained weight from age 30 years to menopause but then lost weight after the menopause experienced risk reductions (RR, 0.77; 95% CI, 0.64-0.92) although perhaps slightly smaller in magnitude than women who maintained their weight in both time intervals (RR, 0.63; 95% CI, 0.55-0.73). Women who gained weight from age 18 to 30 years and then lost weight from age 30 years to menopause had comparable risk reductions (RR, 0.61; 95% CI, 0.46-0.8) with women who maintained their weight in both time intervals (RR, 0.73; 95% CI, 0.64-0.84). Women who gained weight during the period from age 30 years to menopause but who had stable weight after menopause had rates similar to the reference group. These data suggest prevention of weight gain between age 18 years and menopause or weight loss and maintenance during these years reduces risk of postmenopausal breast cancer.
XRCC1 and XRCC3 Polymorphisms and Their Role as Effect Modifiers of Unsaturated Fatty Acids and Antioxidant Intake on Colorectal Adenomas Risk
Authors: Stern Mariana C. , Siegmund Kimberly D. , Corral Román , Haile Robert W.
Published: September 2005

Whereas animal and in vitro studies support a role of unsaturated fatty acids in colon carcinogenesis, the epidemiologic evidence is inconclusive. Using a large sigmoidoscopy-based case-control study (753 cases and 799 controls) in Los Angeles County, we investigated possible associations between single-nucleotide polymorphisms in the XRCC1 (codons 194 Arg/Trp and codon 399 Arg/Gln) and XRCC3 (codon 241 Thr/Met) genes and colorectal adenoma risk and their possible role as modifiers of the effect of monounsaturated fatty acid, the ratio of ω-6/ω-3 polyunsaturated fatty acids, and antioxidant intake. We found no evidence of associations between the XRCC1 codon 194 Arg/Trp or Trp/Trp genotypes and the XRCC3 codon 241 Thr/Met or Met/Met genotypes. Subjects with the XRCC1 Gln/Gln genotype were inversely associated with adenoma risk (odds ratio, 0.6; 95% confidence interval, 0.4-0.9; P = 0.01) when compared with subjects with Arg/Arg and Arg/Gln genotypes combined. We found no evidence of gene-dietary fat interactions for the XRCC3 codon 241 polymorphism. However, our data suggest an XRCC1-unsaturated fat interaction. High monounsaturated fatty acid intake was associated with adenoma risk only among subjects with the XRCC1 codon 194 Arg/Arg and codon 399 Gln/Gln combined genotypes (P for interaction = 0.018). High ω-6/ω-3 polyunsaturated fatty acid ratios were associated with adenoma risk among subjects with the XRCC1 codon 194 Arg/Arg and codon 399 Gln/Gln or the codon 194 Arg/Trp or Trp/Trp and codon 399 Arg/Arg or Arg/Gln combined genotypes (P for interaction = 0.026). These interactions were not modified by antioxidant intake. However, low antioxidant intake was associated with an inverse association only among subjects with the XRCC1 codon 194 Arg/Trp or Trp/Trp and codon 399 Arg/Arg or Arg/Gln combined genotypes (P for interaction = 0.022), which was independent of unsaturated fat intake. Our data suggest that the XRCC1 codon 194 and codon 399 single nucleotide polymorphisms may modify the effect of unsaturated fatty acid and antioxidant intake and that this XRCC1 effect modification may explain, in part, previously reported inconsistencies on the role of unsaturated fatty acids and adenoma risk.