bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from NID2 and HOXA9 Promoter Hypermethylation as Biomarkers for Prevention and Early Detection in Oral Cavity Squamous Cell Carcinoma Tissues and Saliva
Authors: Guerrero-Preston R. , Soudry E. , Acero J. , Orera M. , Moreno-López L. , Macía-Colón G. , Jaffe A. , Berdasco M. , Ili-Gangas C. , Brebi-Mieville P. , Fu Y. , Engstrom C. , Irizarry R.A. , Esteller M. , Westra W. , Koch W. , Califano J. , Sidransky D.
Published: March 2024

Abstract
Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles.

To overcome this lack of relevance, we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and quantitative methylation specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles.

A two stage design consisting of discovery and prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma.

Promoter methylation of KIF1A (κ = 0.64), HOXA9 (κ = 0.60), NID2 (κ = 0.60), and EDNRB (κ = 0.60) had a moderate to substantial agreement with clinical diagnosis in the discovery screen. HOXA9 had 68% sensitivity, 100% specificity, and a 0.81 Area Under the Curve (AUC). NID2 had 71% sensitivity, 100% specificity, and a 0.79 AUC. In the prevalence screen, HOXA9 (κ = 0.82) and NID2 (κ = 0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity, and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity, and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity, and a 0.97 AUC. In saliva, from OSCC cases and controls, HOXA9 had 75% sensitivity, 53% specificity, and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity, and a 0.73 AUC.

This phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies. Cancer Prev Res; 4(7); 1061–72. ©2011 AACR.
Data from Translating Cyclooxygenase Signaling in Patch Heterozygote Mice into a Randomized Clinical Trial in Basal Cell Carcinoma
Authors: Arbiser Jack L.
Published: March 2024

Abstract
This different perspective on Tang et al. (beginning on p. 25 in this issue of the journal) discusses the pivotal role of cyclooxygenase (COX) signaling in the pathogenesis of basal cell carcinoma (BCC). These investigators conducted elegant experiments showing increased BCC burden in patch heterozygous mice overexpressing COX-2 in the epidermis. Genetic deletion of COX-1 or COX-2 resulted in a robust decrease in BCC burden in patch heterozygote mice. They then studied pharmacologic COX inhibition in mice and humans with loss of patch, finding a trend in humans toward decreased BCC burden. This finding has implications for public health. Cancer Prev Res; 3(1); 4–7
Data from Spectrin Repeat Containing Nuclear Envelope 1 and Forkhead Box Protein E1 Are Promising Markers for the Detection of Colorectal Cancer in Blood
Authors: Melotte Veerle , Yi Joo Mi , Lentjes Marjolein H.F.M. , Smits Kim M. , Van Neste Leander , Niessen Hanneke E.C. , Wouters Kim A.D. , Louwagie Joost , Schuebel Kornel E. , Herman James G. , Baylin Stephen B. , van Criekinge Wim , Meijer Gerrit A. , Ahuja Nita , van Engeland Manon
Published: March 2024

Abstract
Identifying biomarkers in body fluids may improve the noninvasive detection of colorectal cancer. Previously, we identified N-Myc downstream-regulated gene 4 (NDRG4) and GATA binding protein 5 (GATA5) methylation as promising biomarkers for colorectal cancer in stool DNA. Here, we examined the utility of NDRG4, GATA5, and two additional markers [Forkhead box protein E1 (FOXE1) and spectrin repeat containing nuclear envelope 1 (SYNE1)] promoter methylation as biomarkers in plasma DNA. Quantitative methylation-specific PCR was performed on plasma DNA from 220 patients with colorectal cancer and 684 noncancer controls, divided in a training set and a test set. Receiver operating characteristic analysis was performed to measure the area under the curve of GATA5, NDRG4, SYNE1, and FOXE1 methylation. Functional assays were performed in SYNE1 and FOXE1 stably transfected cell lines. The sensitivity of NDRG4, GATA5, FOXE1, and SYNE1 methylation in all stages of colorectal cancer (154 cases, 444 controls) was 27% [95% confidence interval (CI), 20%–34%), 18% (95% CI, 12%–24%), 46% (95% CI, 38%–54%), and 47% (95% CI, 39%–55%), with a specificity of 95% (95% CI, 93%–97%), 99% (95% CI, 98%–100%), 93% (95% CI, 91%–95%), and 96% (95% CI, 94%–98%), respectively. Combining SYNE1 and FOXE1, increased the sensitivity to 56% (95% CI, 48%–64%), while the specificity decreased to 90% (95% CI, 87%–93%) in the training set and to 58% sensitivity (95% CI, 46%–70%) and 91% specificity (95% CI, 80%–100%) in a test set (66 cases, 240 controls). SYNE1 overexpression showed no major differences in cell proliferation, migration, and invasion compared with controls. Overexpression of FOXE1 significantly decreased the number of colonies in SW480 and HCT116 cell lines. Overall, our data suggest that SYNE1 and FOXE1 are promising markers for colorectal cancer detection. Cancer Prev Res; 8(2); 157–64. ©2014 AACR.
Data from Zerumbone Induces Heme Oxygenase-1 Expression in Mouse Skin and Cultured Murine Epidermal Cells through Activation of Nrf2
Authors: Shin Jun-Wan , Ohnishi Kohta , Murakami Akira , Lee Jeong-Sang , Kundu Joydeb Kumar , Na Hye-Kyung , Ohigashi Hajime , Surh Young-Joon
Published: March 2024

Abstract
Zerumbone, a sesquiterpene derived from tropical ginger, contains an electrophilic α,β-unsaturated carbonyl moiety and was found to suppress chemically induced papilloma formation in mouse skin. Here, we report that topical application of zerumbone onto dorsal skin of hairless mice induces activation of NF-E2–related factor 2 (Nrf2) and expression of heme oxygenase-1 (HO-1). We compared the levels of HO-1 protein in the skin of zerumbone-treated Nrf2 wild-type and Nrf2 knockout mice, and nrf2-deficient mice expressed HO-1 protein to a much lesser extent than the wild-type animals following topical application of zerumbone. Treatment of mouse epidermal JB6 cells with zerumbone caused a marked increase of Nrf2 nuclear translocation followed by the promoter activity of HO-1, and also enhanced direct binding of Nrf2 to the antioxidant response element. Moreover, knockdown of Nrf2 in JB6 cells diminished the zerumbone-induced upregulation of HO-1. Notably, α-humulene and 8-hydroxy-α-humulene, the structural analogues of zerumbone that lack the α,β-unsaturated carbonyl group, failed to activate Nrf2 and were unable to increase HO-1 expression. Unlike zerumbone, these nonelectrophilic analogues could not suppress the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced JB6 cell transformation and the intracellular accumulation of reactive oxygen species (ROS). Interestingly, when JB6 cells were treated with carbon monoxide–releasing molecule that mimics the HO-1 activity, the TPA-induced ROS production was markedly reduced. Taken together, these findings suggest that upregulation of HO-1 expression by zerumbone is mediated through activation of Nrf2 signaling, which provides a mechanistic basis for the chemopreventive effects of this sesquiterpene on mouse skin carcinogenesis. Cancer Prev Res; 4(6); 860–70. ©2011 AACR.
Data from The Epidermal Growth Factor Receptor Axis: Support for a New Target for Oral Premalignancy
Authors: Rosin Miriam P. , Califano Joseph A.
Published: March 2024

Abstract
This perspective on the report by Benchekroun et al. in this issue of the journal (beginning on page 800) examines new studies of factors in the epidermal growth factor receptor (EGFR) axis (including copy number alterations at the EGFR locus) that potentially predict the development of oral cancer; this work was conducted in a chemoprevention trial cohort of patients with oral premalignant lesions. The new data raise the possibility that a subset of oral premalignant lesions may benefit from specific therapeutic targeting of the EGFR axis. Cancer Prev Res; 3(7); 797–9. ©2010 AACR.
Data from A Novel Combinatorial Nanotechnology-Based Oral Chemopreventive Regimen Demonstrates Significant Suppression of Pancreatic Cancer Neoplastic Lesions
Authors: Grandhi B. Karthik , Thakkar Arvind , Wang Jeffrey , Prabhu Sunil
Published: March 2024

Abstract
Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still less than 5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low-dose combinations of aspirin, curcumin, and sulforaphane (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. The use of three different doses (low, medium, and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50%, and 68.7% respectively; whereas the modified nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed a notable reduction in cell proliferation, the SLN encapsulated ACS regimens showed significant reduction in cell proliferation at 6.3%, 58.6%, and 72.8% as evidenced by proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with BOP control. These studies provide a proof-of-concept for the use of an oral, low-dose, nanotechnology-based combinatorial regimen for the long-term chemoprevention of pancreatic cancer. Cancer Prev Res; 6(10); 1015–25. ©2013 AACR.
Data from Lung Cancer Risk Prediction to Select Smokers for Screening CT—a Model Based on the Italian COSMOS Trial
Authors: Maisonneuve Patrick , Bagnardi Vincenzo , Bellomi Massimo , Spaggiari Lorenzo , Pelosi Giuseppe , Rampinelli Cristiano , Bertolotti Raffaella , Rotmensz Nicole , Field John K. , DeCensi Andrea , Veronesi Giulia
Published: March 2024

Abstract
Screening with low-dose helical computed tomography (CT) has been shown to significantly reduce lung cancer mortality but the optimal target population and time interval to subsequent screening are yet to be defined. We developed two models to stratify individual smokers according to risk of developing lung cancer. We first used the number of lung cancers detected at baseline screening CT in the 5,203 asymptomatic participants of the COSMOS trial to recalibrate the Bach model, which we propose using to select smokers for screening. Next, we incorporated lung nodule characteristics and presence of emphysema identified at baseline CT into the Bach model and proposed the resulting multivariable model to predict lung cancer risk in screened smokers after baseline CT. Age and smoking exposure were the main determinants of lung cancer risk. The recalibrated Bach model accurately predicted lung cancers detected during the first year of screening. Presence of nonsolid nodules (RR = 10.1, 95% CI = 5.57–18.5), nodule size more than 8 mm (RR = 9.89, 95% CI = 5.84–16.8), and emphysema (RR = 2.36, 95% CI = 1.59–3.49) at baseline CT were all significant predictors of subsequent lung cancers. Incorporation of these variables into the Bach model increased the predictive value of the multivariable model (c-index = 0.759, internal validation). The recalibrated Bach model seems suitable for selecting the higher risk population for recruitment for large-scale CT screening. The Bach model incorporating CT findings at baseline screening could help defining the time interval to subsequent screening in individual participants. Further studies are necessary to validate these models. Cancer Prev Res; 4(11); 1778–89. ©2011 AACR.
Data from Classifying Patients for Breast Cancer by Detection of Autoantibodies against a Panel of Conformation-Carrying Antigens
Authors: Evans Rick L. , Pottala James V. , Egland Kristi A.
Published: March 2024

Abstract
Patients with breast cancer elicit an autoantibody response against cancer proteins, which reflects and amplifies the cellular changes associated with tumorigenesis. Detection of autoantibodies in plasma may provide a minimally invasive mechanism for early detection of breast cancer. To identify cancer proteins that elicit a humoral response, we generated a cDNA library enriched for breast cancer genes that encode membrane and secreted proteins, which are more likely to induce an antibody response compared with intracellular proteins. To generate conformation-carrying antigens that are efficiently recognized by patients' antibodies, a eukaryotic expression strategy was established. Plasma from 200 patients with breast cancer and 200 age-matched healthy controls were measured for autoantibody activity against 20 different antigens designed to have conformational epitopes using ELISA. A conditional logistic regression model was used to select a combination of autoantibody responses against the 20 different antigens to classify patients with breast cancer from healthy controls. The best combination included ANGPTL4, DKK1, GAL1, MUC1, GFRA1, GRN, and LRRC15; however, autoantibody responses against GFRA1, GRN, and LRRC15 were inversely correlated with breast cancer. When the autoantibody responses against the 7 antigens were added to the base model, including age, BMI, race and current smoking status, the assay had the following diagnostic capabilities: c-stat (95% CI), 0.82 (0.78–0.86); sensitivity, 73%; specificity, 76%; and positive likelihood ratio (95% CI), 3.04 (2.34–3.94). The model was calibrated across risk deciles (Hosmer–Lemeshow, P = 0.13) and performed well in specific subtypes of breast cancer including estrogen receptor positive, HER-2 positive, invasive, in situ and tumor sizes >1 cm. Cancer Prev Res; 7(5); 545–55. ©2014 AACR.
Data from Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells
Authors: Colin Didier , Limagne Emeric , Jeanningros Sylvie , Jacquel Arnaud , Lizard Gérard , Athias Anne , Gambert Philippe , Hichami Aziz , Latruffe Norbert , Solary Eric , Delmas Dominique
Published: March 2024

Abstract
trans-Resveratrol has been proposed to prevent tumor growth and to sensitize cancer cells to anticancer agents. Polyphenol entry into the cells has remained poorly understood. Here, we show that [3H]-resveratrol enters colon cancer cells (SW480, SW620, HT29) and leukemia U937 cells through a monensin (5–20 μmol/L) -sensitive process that suggests clathrin-independent endocytosis. Uptake of the molecule can be prevented by methyl-β-cyclodextrin (2–12 mg/mL), nystatin (12 ng/mL), and filipin (1 μg/mL), which all disrupt plasma membrane lipid rafts. Accordingly, radiolabeled resveratrol accumulates in sphingomyelin- and cholesterol-enriched cell fractions. Interestingly, extracellular signal–regulated kinases (ERK), c-Jun NH2-terminal kinases (JNK), and Akt also accumulate in lipid rafts on resveratrol exposure (IC50 at 48 h ≈ 30 μmol/L in SW480 and U937 cells). In these rafts also, resveratrol promotes the recruitment, by the integrin αVβ3 (revealed by coimmunoprecipitation with an anti-integrin αVβ3 antibody), of signaling molecules that include the FAK (focal adhesion kinase), Fyn, Grb2, Ras, and SOS proteins. Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis is prevented by endocytosis inhibitors, lipid raft–disrupting molecules, and the integrin antagonist peptide arginine-glycine-aspartate (500 nmol/L). Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death. Cancer Prev Res; 4(7); 1095–106. ©2011 AACR.
Data from Cucurbitacin B Alters the Expression of Tumor-Related Genes by Epigenetic Modifications in NSCLC and Inhibits NNK-Induced Lung Tumorigenesis
Authors: Shukla Samriddhi , Khan Sajid , Kumar Sudhir , Sinha Sonam , Farhan Mohd. , Bora Himangsu K. , Maurya Rakesh , Meeran Syed Musthapa
Published: March 2024

Abstract
Non–small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors is effective against various cancers, including lung cancer. However, optimizing the synergistic dose regime is very difficult and involves adverse side effects. Therefore, in this study, we have shown that cucurbitacin B (CuB), a single bioactive triterpenoid compound, inhibits both DNMTs and HDACs starting at a very low dose of 60 nmol/L in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSG) such as CDKN1A and CDKN2A, as well as downregulation of oncogenes c-MYC and K-RAS and key tumor promoter gene (TPG), human telomerase reverse transcriptase (hTERT). The upregulation of TSGs and downregulation of TPG were consistently correlated with the alterations in their promoter methylation and histone modifications. This altered expression of TPG and TSGs is, at least in part, responsible for the inhibition of cellular proliferation and induction of cellular apoptosis in NSCLC. Furthermore, CuB treatment significantly inhibited the tumor incidence and multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, which was associated with the induction of apoptosis and inhibition of hyperproliferation in the lung tissues. Together, our study provides new insight into the CuB-mediated epigenetic alterations and its chemotherapeutic effects on lung cancer. Cancer Prev Res; 8(6); 552–62. ©2015 AACR.
Data from CYLD Inhibits Tumorigenesis and Metastasis by Blocking JNK/AP1 Signaling at Multiple Levels
Authors: de Marval Paula Miliani , Lutfeali Shazia , Jin Jane Y. , Leshin Benjamin , Selim M. Angelica , Zhang Jennifer Y.
Published: March 2024

Abstract
CYLD has been recognized as a tumor suppressor due to its dominant genetic linkage to multiple types of epidermal tumors and a range of other cancers. The molecular mechanisms governing CYLD control of skin cancer are still unclear. Here, we showed that K14-driven epidermal expression of a patient-relevant and catalytically deficient CYLD truncated mutant (CYLDm) sensitized mice to skin tumor development in response to 7,12-dimethylbenz[α]anthracene (DMBA)/(12-O-tetradecanoylphorbol-13-acetate) TPA challenge. Tumors developed on transgenic mice were prone to malignant progression and lymph node metastasis and displayed increased activation of c-Jun-NH2-kinase (JNK) and the downstream c-Jun and c-Fos proteins. Most importantly, topical application of a pharmacologic JNK inhibitor significantly reduced tumor development and abolished metastasis in the transgenic mice. Further in line with these animal data, exogenous expression of CYLDm in A431, a human squamous cell carcinoma (SCC) cell line, markedly enhanced cell growth, migration, and subcutaneous tumor growth in an AP1-depdendent manner. In contrast, expression of the wild-type CYLD inhibited SCC tumorigenesis and AP1 function. Most importantly, CYLDm not only increased JNK activation but also induced an upregulation of K63 ubiquitination on both c-Jun and c-Fos, leading to sustained AP1 activation. Our findings uncovered c-Jun and c-Fos as novel CYLD targets and underscore that CYLD controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels. Cancer Prev Res; 4(6); 851–9. ©2011 AACR.
Data from How Do We Safely Get People to Stop Smoking?
Authors: Lam David C.L. , Minna John D.
Published: March 2024

Abstract
Nicotine replacement therapy (NRT) is a valuable, proven, and U.S. Food and Drug Administration–approved tool for smoking cessation. However, the discoveries of functional nicotinic acetylcholine receptors (nAChR) on lung epithelial and cancer cells and of nAChR polymorphisms associated with lung cancer risk, in addition to a large number of preclinical studies indicating that nicotine may promote or facilitate cancer development and growth, have prompted concern that NRT, although important for smoking cessation, may actually augment lung carcinogenesis. Therefore, it is of great public health interest that two independent studies reported in this issue of the journal (Murphy and colleagues, beginning on page 1752, and Maier and colleagues, beginning on page 1743) showed that nicotine given in drinking water at a dose to achieve blood concentrations in mice similar to those achieved in people receiving NRT did not enhance lung carcinogenesis or tumor growth in several mouse models of lung cancer. Effective non-nicotine alternatives to NRT, such as varenicline and bupropion, are also available and perhaps better than NRT for smoking cessation therapy. In the near future, nicotine vaccines will likely be added to the smoking cessation armamentarium. However, the normal and pathophysiologic role of nicotine, nAChRs, and the signaling pathways they activate in lung epithelial cells and lung cancer still requires elucidation. Cancer Prev Res; 4(11); 1724–7. ©2011 AACR.
Data from New Role of (−)-Epicatechin in Enhancing the Induction of Growth Inhibition and Apoptosis in Human Lung Cancer Cells by Curcumin
Authors: Saha Achinto , Kuzuhara Takashi , Echigo Noriko , Suganuma Masami , Fujiki Hirota
Published: March 2024

Abstract
Curcumin, a phenolic compound isolated from the plant Curcuma longa (Linn), is ingested every day in the Indian subcontinent and is well reported to possess cancer-preventive activity. To achieve effective cancer prevention with curcumin, we need to find a new method to enhance the effects of curcumin in the diet. Based on our evidence that (−)-epicatechin (EC), an inert catechin, enhances the cancer-preventive activity of green tea catechins, we studied the enhancing effects of EC on inductions of growth inhibition and apoptosis in human lung cancer cell lines PC-9 and A549 with curcumin. The combination of curcumin with EC significantly increased the inhibition of cell growth compared with curcumin or EC alone. The combination similarly increased both apoptosis and expression of GADD153 and GADD45 genes, associated with their enhanced protein production. Knockdown of GADD153 or GADD45 by small interfering RNA abrogated the apoptosis induction and growth inhibition induced by the combination, indicating the crucial role of their upregulation. Treatments of PC-9 cells with c-Jun-NH2-kinase inhibitor SP600125, with p38 mitogen-activated protein kinase inhibitor SB202190 and with PD98059 (extracellular signal-regulated kinase 1/2 inhibitor) all increased the upregulation of GADD153 and GADD45 genes by the combination. Because EC was previously shown to enhance the incorporation of EGCG into PC-9 cells, we think that EC has similar effects on curcumin. This report is the first report on the enhancing effects of EC on curcumin, and the data suggest that EC plays a significant role in the enhancement of the cancer-preventive activity of curcumin in the diet. Cancer Prev Res; 3(8); 953–62. ©2010 AACR.
Data from Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic
Authors: Meyskens Frank L. , Curt Gregory A. , Brenner Dean E. , Gordon Gary , Herberman Ronald B. , Finn Olivera , Kelloff Gary J. , Khleif Samir N. , Sigman Caroline C. , Szabo Eva
Published: March 2024

Abstract
This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs. Cancer Prev Res; 4(3); 311–23. ©2011 AACR.
Data from Epigenetic Alteration of DNA in Mucosal Wash Fluid Predicts Invasiveness of Colorectal Tumors
Authors: Kamimae Seiko , Yamamoto Eiichiro , Yamano Hiro-o , Nojima Masanori , Suzuki Hiromu , Ashida Masami , Hatahira Tomo , Sato Akiko , Kimura Tomoaki , Yoshikawa Kenjiro , Harada Taku , Hayashi Seiko , Takamaru Hiroyuki , Maruyama Reo , Kai Masahiro , Nishiwaki Morie , Sugai Tamotsu , Sasaki Yasushi , Tokino Takashi , Shinomura Yasuhisa , Imai Kohzoh , Toyota Minoru
Published: March 2024

Abstract
Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors. Cancer Prev Res; 4(5); 674–83. ©2011 AACR.
Data from Social Stress Promotes and γ-Aminobutyric Acid Inhibits Tumor Growth in Mouse Models of Non–Small Cell Lung Cancer
Authors: Al-Wadei Hussein A.N. , Plummer Howard K. , Ullah Mohammad F. , Unger Benjamin , Brody Joel R. , Schuller Hildegard M.
Published: March 2024

Abstract
Psychologic distress is associated with increased lung cancer incidence and mortality. We have shown that non–small cell lung cancer (NSCLC) cells in vitro are stimulated by the cyclic AMP (cAMP)-dependent activation of cAMP-responsive element binding protein (CREB) and extracellular signal–regulated kinase (ERK) downstream of β-adrenergic receptors and that this pathway is inhibited by the neurotransmitter γ-aminobutyric acid (GABA). Because the stress neurotransmitters noradrenalin and adrenalin are β-adrenergic agonists, the current study has tested the hypothesis that social stress stimulates NSCLC growth in vivo and that GABA inhibits this effect. Social stress was induced in mice carrying xenografts from two NSCLC cell lines in the presence and absence of treatment with GABA. Xenograft sizes were measured after 30 days. Noradrenalin, adrenalin, cortisol, GABA, and cAMP were measured in blood and tumor tissues by immunoassays. Expression of nicotinic receptors in the xenografts was assessed by real-time PCR and Western blotting. Protein expression of phospho (p)-CREB, CREB, phospho (p)-ERK, ERK, and glutamate decarboxylase (GAD) 65 and 67 were determined by Western blotting. Xenograft sizes in stress-exposed mice were significantly increased. Nicotinic acetylcholine receptor (nAChR) subunits α3, α4, α5, and α7 in xenograft tissues showed posttranscriptional induction. Noradrenalin, adrenalin, and cortisol were elevated in serum and xenograft tissue whereas GABA was suppressed. Levels of cAMP, p-CREB, and p-ERK were increased whereas GAD65 and GAD67 were suppressed in tumor tissue. Treatment with GABA reversed the effects of stress. Our findings suggest that social stress stimulates NSCLC by increasing nAChR-mediated stress neurotransmitter signaling and that GABA is a promising novel agent for NSCLC intervention. Cancer Prev Res; 5(2); 189–96. ©2011 AACR.
Data from A DNA Vaccine against ERBB2 Impairs Chemical Carcinogenesis in Random-Bred Hamsters
Authors: Berta Giovanni N. , Sprio Andrea E. , Iezzi Manuela , Spadaro Michela , Cappia Susanna , Salamone Paolina , Di Scipio Federica , Mognetti Barbara , Papotti Mauro , Musiani Piero , Forni Guido , Cavallo Federica
Published: March 2024

Abstract
Vaccines against oncoantigens halt early neoplastic lesions in several cancer-prone, genetically engineered mouse models, whereas their ability to prevent chemical carcinogenesis has not been explored. This is a significant issue, as exposure to chemical mutagens is responsible for a substantial percentage of cancers worldwide. Here, we show that the archetypal oncoantigen ERBB2 is transiently overexpressed in Syrian hamsters during the early stages of 7,12-dimethylbenz[α]anthracene (DMBA)-induced oral carcinogenesis. Repeated DNA vaccinations against ERBB2 significantly reduce the number, size, and severity of oral lesions in a manner directly proportional to the anti-ERBB2 antibody response. These results support the prospects of vaccines as a fresh strategy in the management of individuals at risk for exposure to defined carcinogenic agents. Cancer Prev Res; 4(7); 994–1001. ©2011 AACR.
Data from Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism
Authors: Karoor Vijaya , Le Mysan , Merrick Daniel , Fagan Karen A. , Dempsey Edward C. , Miller York E.
Published: March 2024

Abstract
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD. Cancer Prev Res; 5(8); 1061–71. ©2012 AACR.
Data from Plasma Tocopherols and Risk of Prostate Cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT)
Authors: Albanes Demetrius , Till Cathee , Klein Eric A. , Goodman Phyllis J. , Mondul Alison M. , Weinstein Stephanie J. , Taylor Philip R. , Parnes Howard L. , Gaziano J. Michael , Song Xiaoling , Fleshner Neil E. , Brown Powel H. , Meyskens Frank L. , Thompson Ian M.
Published: March 2024

Abstract
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We, therefore, examined whether presupplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case–cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0–7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88–1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44–1.62; P-trend = 0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29–3.22; P-trend = 0.005]. A positive plasma α-tocopherol–prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7–10; overall Q5 HR, 1.59; 95% CI, 1.13–2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32–3.40; P-trend = 0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between α-tocopherol and selenium itself or selenomethionine. Cancer Prev Res; 7(9); 886–95. ©2014 AACR.
Data from Time to Think Outside the (Genetic) Box
Authors: Issa Jean-Pierre J. , Garber Judy E.
Published: March 2024

Abstract
Many patients develop cancers that have clinical features of inherited syndromes (e.g., young age of onset and unique pathology) but lack mutations in the genes characteristic of the disease. In this issue of the journal, Wong et al. report that somatic epigenetic inactivation could explain some such cases in the setting of BRCA1-associated breast cancer. Here, we discuss the implications of this work in terms of the etiology, risk, and potential prevention of cancer. Cancer Prev Res; 4(1); 6–8. ©2011 AACR.
Data from Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis
Authors: McIlhatton Michael A. , Murnan Kevin , Carson Daniel , Boivin Gregory P. , Croce Carlo M. , Groden Joanna
Published: March 2024

Abstract
Although disruption of DNA repair capacity is unquestionably associated with cancer susceptibility in humans and model organisms, it remains unclear if the inherent tumor phenotypes of DNA repair deficiency syndromes can be regulated by manipulating DNA repair pathways. Loss-of-function mutations in BLM, a member of the RecQ helicase family, cause Bloom's syndrome (BS), a rare, recessive genetic disorder that predisposes to many types of cancer. BLM functions in many aspects of DNA homeostasis, including the suppression of homologous recombination (HR) in somatic cells. We investigated whether BLM overexpression, in contrast with loss-of-function mutations, attenuated the intestinal tumor phenotypes of ApcMin/+ and ApcMin/+;Msh2−/− mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (BLM-Tg) and crossed it onto both backgrounds. BLM-Tg decreased adenoma incidence in a dose-dependent manner in our ApcMin/+ model of FAP, although levels of GIN were unaffected and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in ApcMin/+;Msh2−/− mice. We used the pink-eyed unstable (pun) mouse model to demonstrate that increasing BLM dosage in vivo lowered endogenous levels of HR by 2-fold. Our data suggest that attenuation of the Min phenotype is achieved through a direct effect of BLM-Tg on the HR repair pathway. These findings demonstrate that HR can be manipulated in vivo to modulate tumor formation at the organismal level. Our data suggest that lowering HR frequencies may have positive therapeutic outcomes in the context of specific hereditary cancer predisposition syndromes, exemplified by FAP. Cancer Prev Res; 8(7); 650–6. ©2015 AACR.
Data from Naproxen Induces Cell-Cycle Arrest and Apoptosis in Human Urinary Bladder Cancer Cell Lines and Chemically Induced Cancers by Targeting PI3K
Authors: Kim Mi-Sung , Kim Jong-Eun , Lim Do Young , Huang Zunnan , Chen Hanyong , Langfald Alyssa , Lubet Ronald A. , Grubbs Clinton J. , Dong Zigang , Bode Ann M.
Published: March 2024

Abstract
Naproxen [(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid] is a potent nonsteroidal anti-inflammatory drug that inhibits both COX-1 and COX-2 and is widely used as an over-the-counter medication. Naproxen exhibits analgesic, antipyretic, and anti-inflammatory activities. Naproxen, as well as other nonsteroidal anti-inflammatory drug, has been reported to be effective in the prevention of urinary bladder cancer in rodents. However, potential targets other than the COX isozymes have not been reported. We examined potential additional targets in urinary bladder cancer cells and in rat bladder cancers. Computer kinase profiling results suggested that phosphoinositide 3-kinase (PI3K) is a potential target for naproxen. In vitro kinase assay data revealed that naproxen interacts with PI3K and inhibits its kinase activity. Pull-down binding assay data confirmed that PI3K directly binds with naproxen in vitro and ex vivo. Western blot data showed that naproxen decreased phosphorylation of Akt, and subsequently decreased Akt signaling in UM-UC-5 and UM-UC-14 urinary bladder cancer cells. Furthermore, naproxen suppressed anchorage-independent cell growth and decreased cell viability by targeting PI3K in both cell lines. Naproxen caused an accumulation of cells at the G1 phase mediated through cyclin-dependent kinase 4, cyclin D1, and p21. Moreover, naproxen induced significant apoptosis, accompanied with increased levels of cleaved caspase-3, caspase-7, and PARP in both cell types. Naproxen-induced cell death was mainly because of apoptosis in which a prominent downregulation of Bcl-2 and upregulation of Bax were involved. Naproxen also caused apoptosis and inhibited Akt phosphorylation in rat urinary bladder cancers induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine. Cancer Prev Res; 7(2); 236–45. ©2013 AACR.
Data from Safety and Chemopreventive Effect of Polyphenon E in Preventing Early and Metastatic Progression of Prostate Cancer in TRAMP Mice
Authors: Kim Seung Joon , Amankwah Ernest , Connors Shahnjayla , Park Hyun Y. , Rincon Maria , Cornnell Heather , Chornokur Ganna , Hashim Arig Ibrahim , Choi Junsung , Tsai Ya-Yu , Engelman Robert W. , Kumar Nagi , Park Jong Y.
Published: March 2024

Abstract
Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer. Cancer Prev Res; 7(4); 435–44. ©2014 AACR.
Data from Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention
Authors: Thomasset Sarah , Berry David P. , Cai Hong , West Kevin , Marczylo Tim H. , Marsden Debbie , Brown Karen , Dennison Ashley , Garcea Giuseppe , Miller Andrew , Hemingway David , Steward William P. , Gescher Andreas J.
Published: March 2024

Abstract
Naturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching ∼179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in ApcMin mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing <0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.
Data from Oncogenic Function and Early Detection Potential of miRNA-10b in Oral Cancer as Identified by microRNA Profiling
Authors: Lu Ya-Ching , Chen Yin-Ju , Wang Hung-Ming , Tsai Chi-Ying , Chen Wen-Ho , Huang Yu-Chen , Fan Kang-Hsing , Tsai Chi-Neu , Huang Shiang-Fu , Kang Chung-Jan , Chang Joseph Tung-Chieh , Cheng Ann-Joy
Published: March 2024

Abstract
The miRNA participates in a variety of biologic processes, and dysregulation of miRNA is associated with malignant transformation. In this study, we determined specific profile of miRNA associated with oral cancer by using miRNA array screening method. There were 23 miRNAs found with considerably differential expressions between six oral cancer cell lines and five lines of normal oral keratinocytes, in which, 10 miRNAs showed the highest significant difference after independent examination by reverse transcription quantitative PCR. Eight molecules were upregulated, miR-10b, miR-196a, miR-196b, miR-582-5p, miR-15b, miR-301, miR-148b, and miR-128a, and two molecules, miR-503 and miR-31, were downregulated. The most upregulated miR-10b was further examined, and its functions were characterized in two oral cancer cell lines. The miR-10b actively promotes cell migration (2.6- to 3.6-fold) and invasion (1.7- to 1.9-fold) but has minimal effect on cell growth or chemo-/radiosensitivity. Furthermore, miR-10b was considerably elevated in the plasma of xenografted tumor mice (20-fold). This upregulation of miR-10b in plasma was further shown in the patients with oral cancer [P < 0.0001, area under curve (AUC) = 0.932] and precancer lesions (P < 0.0001, AUC = 0.967), suggesting that miR-10b possesses a high potential to discriminate the normal subjects. In conclusion, we have identified at least 10 miRNAs significantly associated with oral cancer, including the most elevated miR-10b. The miR-10b actively participates in cancer formation by promoting cell migration and invasion. Our study using clinical samples suggests that plasma miR-10b has high potential as an early detection marker for oral cancer. Cancer Prev Res; 5(4); 665–74. ©2012 AACR.
Data from Unfolded Protein Response Signaling and MAP Kinase Pathways Underlie Pathogenesis of Arsenic-Induced Cutaneous Inflammation
Authors: Li Changzhao , Xu Jianmin , Li Fugui , Chaudhary Sandeep C. , Weng Zhiping , Wen Jianming , Elmets Craig A. , Ahsan Habibul , Athar Mohammad
Published: March 2024

Abstract
Arsenic exposure through drinking water is a major global public health problem and is associated with an enhanced risk of various cancers including skin cancer. In human skin, arsenic induces precancerous melanosis and keratosis, which may progress to basal cell and squamous cell carcinoma. However, the mechanism by which these pathophysiologic alterations occur remains elusive. In this study, we showed that subchronic arsenic exposure to SKH-1 mice induced unfolded protein response (UPR) signaling regulated by proteins, inositol-requiring enzyme-1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6). Arsenic activated all three UPR regulatory proteins in the skin. Arsenic induced IRE1 phosphorylation which resulted in augmented splicing of X-box binding protein 1 (XBP-1) leading to its migration to the nucleus, and also enhanced transcriptional activation of downstream target proteins. Hyperphosphorylation of PERK which induces eukaryotic translation initial factor 2α (eIF2α) in a phosphorylation-dependent manner enhanced translation of ATF4, in addition to augmenting proteolytic activation of ATF6 in arsenic-treated skin. A similar increase in the expression of CHOP was observed. Enhanced XBP-1s, ATF4, and ATF6 regulated downstream chaperones GRP94 and GRP78. In addition, arsenic induced inflammation-related p38/MAPKAPK-2 MAPK signaling and alterations in Th-1/Th-2/Th-17 cytokines/chemokines and their receptors. Antioxidant N-acetyl cysteine blocked arsenic-induced reactive oxygen species, with a concomitant attenuation of UPR and mitogen-activated protein kinase (MAPK) signaling and proinflammatory cytokine/chemokine signatures. Our results identify novel pathways involved in the pathogenesis of arsenic-med iated cutaneous inflammation which may also be related to enhanced cancer risk in arsenic exposed cohorts. Cancer Prev Res; 4(12); 2101–9. ©2011 AACR.