bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Aspirin and Familial Adenomatous Polyposis: Coming Full Circle
Authors: Chan Andrew T.
Published: March 2024

Abstract
This perspective discusses the clinical trial reported by Burn and colleagues in this issue of the journal (beginning on page 655), which assessed aspirin and resistant starch for the prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP). The findings are examined in the context of previous clinical trials of aspirin in patients with sporadic adenomas and of sulindac or celecoxib in patients with FAP. This newly reported work raises important considerations of a role for aspirin in the clinical management of FAP patients and adds to considerations of a role for aspirin in the chemoprevention of colorectal cancer among broader populations. Cancer Prev Res; 4(5); 623–7. ©2011 AACR.
Data from Class I HDACs Are Mediators of Smoke Carcinogen–Induced Stabilization of DNMT1 and Serve as Promising Targets for Chemoprevention of Lung Cancer
Authors: Brodie Seth A. , Li Ge , El-Kommos Adam , Kang Hyunseok , Ramalingam Suresh S. , Behera Madhusmita , Gandhi Khanjan , Kowalski Jeanne , Sica Gabriel L. , Khuri Fadlo R. , Vertino Paula M. , Brandes Johann C.
Published: March 2024

Abstract
DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention. Cancer Prev Res; 7(3); 351–61. ©2014 AACR.
Data from Revisit of Field Cancerization in Squamous Cell Carcinoma of Upper Aerodigestive Tract: Better Risk Assessment with Epigenetic Markers
Authors: Lee Yi-Chia , Wang Hsiu-Po , Wang Cheng-Ping , Ko Jenq-Yuh , Lee Jang-Ming , Chiu Han-Mo , Lin Jaw-Town , Yamashita Satoshi , Oka Daiji , Watanabe Naoko , Matsuda Yasunori , Ushijima Toshikazu , Wu Ming-Shiang
Published: March 2024

Abstract
We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P = 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%–81%), 74% specificity (66%–82%), and 80% area under the curve (67%–91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%–79%), 75% (67%–83%), and 83% (79%–87%); and both together had values of 82% (76%–88%), 81% (74%–88%), and 91% (88%–94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%–85%). We concluded that epigenetics could improve the accuracies of risk assessment. Cancer Prev Res; 4(12); 1982–92. ©2011 AACR.
Data from Targeting Ornithine Decarboxylase for the Prevention of Nonmelanoma Skin Cancer in Humans
Authors: Elmets Craig A. , Athar Mohammad
Published: March 2024

Abstract
Bailey et al. report in this issue of the journal (beginning on page 35) one of the first successful trials of basal cell carcinoma (BCC) prevention. Oral α-difluoromethyl-dl-ornithine (DFMO) reduced new BCCs in patients with a prior history of nonmelanoma skin cancer. DFMO is an inhibitor of ornithine decarboxylase, a key enzyme in the polyamine biosynthetic pathway. This perspective on Bailey et al. discusses our knowledge of the contribution of polyamines to BCC pathogenesis, how this knowledge advanced the development of a new method to prevent BCCs, and prospects for future studies of DFMO in BCC prevention. Cancer Prev Res; 3(1); 8–11
Data from Body Mass Index and the Risk for Developing Invasive Breast Cancer among High-Risk Women in NSABP P-1 and STAR Breast Cancer Prevention Trials
Authors: Cecchini Reena S. , Costantino Joseph P. , Cauley Jane A. , Cronin Walter M. , Wickerham D. Lawrence , Land Stephanie R. , Weissfeld Joel L. , Wolmark Norman
Published: March 2024

Abstract
High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, whereas women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (P = 0.01). Compared with BMI less than 25, adjusted HRs for premenopausal women were 1.59 for BMI 25 to 29.9 and 1.70 for BMI 30 or more. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than 35 years, but not postmenopausal women. Cancer Prev Res; 5(4); 583–92. ©2012 AACR.
Data from Resveratrol-Induced Apoptosis Is Mediated by Early Growth Response-1, Krüppel-Like Factor 4, and Activating Transcription Factor 3
Authors: Whitlock Nichelle C. , Bahn Jae Hoon , Lee Seong-Ho , Eling Thomas E. , Baek Seung Joon
Published: March 2024

Abstract
Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess antitumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment. We confirmed that resveratrol upregulates ATF3 expression, both at the mRNA and protein level, and showed resveratrol involvement in ATF3 transcriptional regulation. Analysis of the ATF3 promoter revealed the importance of early growth response-1 (Egr-1; located at −245 to −236) and Krüppel-like factor 4 (KLF4; located at −178 to −174) putative binding sites in resveratrol-mediated ATF3 transactivation. Specificity of these sites to the Egr-1 and KLF4 protein was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Resveratrol increased Egr-1 and KLF4 expression, which preceded ATF3 expression, and further suggests Egr-1 and KLF4 involvement in resveratrol-mediated activity. We provide evidence for Egr-1 and KLF4 interaction in the presence of resveratrol, which may facilitate ATF3 transcriptional regulation by this compound. Furthermore, we demonstrate that induction of apoptosis by resveratrol is mediated, in part, by increased ATF3 expression. Taken together, these results provide a novel mechanism by which resveratrol induces ATF3 expression and represent an additional explanation of how resveratrol exerts its antitumorigenic effects in human colorectal cancer cells. Cancer Prev Res; 4(1); 116–27. ©2011 AACR.
Data from Metformin and Cancer Stem Cells: Old Drug, New Targets
Authors: Bednar Filip , Simeone Diane M.
Published: March 2024

Abstract
In this issue of the journal, Bao and colleagues report (beginning on page 355) that the antidiabetic drug metformin targets pancreatic cancer stem cells through, at least partially, the modulation of miRNA expression and subsequent regulation of stem cell renewal and signaling factors. In this Perspective, we briefly discuss the cancer stem cell hypothesis, its clinical relevance, and how targeting the mTOR pathway may yield an avenue for disrupting the cancer stem cell compartment and thus yield long-term therapeutic benefit in multiple cancers. Cancer Prev Res; 5(3); 351–4. ©2012 AACR.
Data from Chemoprevention of B-Cell Lymphomas by Inhibition of the Myc Target Spermidine Synthase
Authors: Forshell TachaZi Plym , Rimpi Sara , Nilsson Jonas A.
Published: March 2024

Abstract
The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in λ-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration. Cancer Prev Res; 3(2); 140–7
Data from A Multiplexable, Microfluidic Platform for the Rapid Quantitation of a Biomarker Panel for Early Ovarian Cancer Detection at the Point-of-Care
Authors: Shadfan Basil H. , Simmons Archana R. , Simmons Glennon W. , Ho Andy , Wong Jorge , Lu Karen H. , Bast Robert C. , McDevitt John T.
Published: March 2024

Abstract
Point-of-care (POC) diagnostic platforms have the potential to enable low-cost, large-scale screening. As no single biomarker is shed by all ovarian cancers, multiplexed biomarker panels promise improved sensitivity and specificity to address the unmet need for early detection of ovarian cancer. We have configured the programmable bio-nano-chip (p-BNC)—a multiplexable, microfluidic, modular platform—to quantify a novel multi-marker panel comprising CA125, HE4, MMP-7, and CA72-4. The p-BNC is a bead-based immunoanalyzer system with a credit-card–sized footprint that integrates automated sample metering, bubble and debris removal, reagent storage and waste disposal, permitting POC analysis. Multiplexed p-BNC immunoassays demonstrated high specificity, low cross-reactivity, low limits of detection suitable for early detection, and a short analysis time of 43 minutes. Day-to-day variability, a critical factor for longitudinally monitoring biomarkers, ranged between 5.4% and 10.5%, well below the biologic variation for all four markers. Biomarker concentrations for 31 late-stage sera correlated well (R2 = 0.71 to 0.93 for various biomarkers) with values obtained on the Luminex platform. In a 31 patient cohort encompassing early- and late-stage ovarian cancers along with benign and healthy controls, the multiplexed p-BNC panel was able to distinguish cases from controls with 68.7% sensitivity at 80% specificity. Utility for longitudinal biomarker monitoring was demonstrated with prediagnostic plasma from 2 cases and 4 controls. Taken together, the p-BNC shows strong promise as a diagnostic tool for large-scale screening that takes advantage of faster results and lower costs while leveraging possible improvement in sensitivity and specificity from biomarker panels. Cancer Prev Res; 8(1); 37–48. ©2014 AACR.
Data from Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice
Authors: Shimizu Masahito , Sakai Hiroyasu , Shirakami Yohei , Iwasa Junpei , Yasuda Yoichi , Kubota Masaya , Takai Koji , Tsurumi Hisashi , Tanaka Takuji , Moriwaki Hisataka
Published: March 2024

Abstract
Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) α due to phosphorylation by Ras/MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRα, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J- +Leprdb/+Leprdb (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared with basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK (extracellular signal-regulated kinase) and RXRα proteins in the livers of experimental mice. It also increased the expression of RAR β and p21CIP1 mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRα function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin decreased by ACR treatment, whereas the quantitative insulin sensitivity check index (QUICKI) values increased, indicating improved insulin sensitivity. The serum levels of TNF-α and the expression levels of TNF- α, IL-6, and IL-1 β mRNA in the livers of DEN-treated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. ACR may be, therefore, useful in the chemoprevention of obesity-related HCC. Cancer Prev Res; 4(1); 128–36. ©2010 AACR.
Data from Concordant DNA Methylation in Synchronous Colorectal Carcinomas
Authors: Konishi Kazuo , Shen Lanlan , Jelinek Jaroslav , Watanabe Yoshiyuki , Ahmed Saira , Kaneko Kazuhiro , Kogo Mari , Takano Toshihumi , Imawari Michio , Hamilton Stanley R. , Issa Jean-Pierre J.
Published: March 2024

Abstract
Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.
Data from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer
Authors: Paul Olson Terrah J. , Hadac Jamie N. , Sievers Chelsie K. , Leystra Alyssa A. , Deming Dustin A. , Zahm Christopher D. , Albrecht Dawn M. , Nomura Alice , Nettekoven Laura A. , Plesh Lauren K. , Clipson Linda , Sullivan Ruth , Newton Michael A. , Schelman William R. , Halberg Richard B.
Published: March 2024

Abstract
Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived ApcMin/+ mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies. Cancer Prev Res; 7(1); 105–13. ©2013 AACR.
Data from Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders
Authors: Gandini Sara , Puntoni Matteo , Heckman-Stoddard Brandy M. , Dunn Barbara K. , Ford Leslie , DeCensi Andrea , Szabo Eva
Published: March 2024

Abstract
Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I2 = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I2 = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I2 = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I2 = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.
Data from Dietary Soy Effects on Mammary Gland Development during the Pubertal Transition in Nonhuman Primates
Authors: Dewi Fitriya N. , Wood Charles E. , Lees Cynthia J. , Willson Cynthia J. , Register Thomas C. , Tooze Janet A. , Franke Adrian A. , Cline J. Mark
Published: March 2024

Abstract
While epidemiologic studies suggest that soy intake early in life may reduce breast cancer risk, there are also concerns that exposure to soy isoflavones during childhood may alter pubertal development and hormonal profiles. Here, we assessed the effect of a high-soy diet on pubertal breast development, sex hormones, and growth in a nonhuman primate model. Pubertal female cynomolgus monkeys were randomized to receive a diet modeled on a typical North American diet with one of two protein sources for approximately 4.5 years: (i) casein/lactalbumin (CL, n = 12, as control) or (ii) soy protein isolate with a human equivalent dose of 120 mg/d isoflavones (SOY, n = 17), which is comparable to approximately four servings of soy foods. Pubertal exposure to the SOY diet did not alter onset of menarche, indicators of growth and pubertal progression, or circulating estradiol and progesterone concentrations. Greater endometrial area was seen in the SOY group on the first of four postmenarchal ultrasound measurements (P < 0.05). There was a subtle effect of diet on breast differentiation whereby the SOY group showed higher numbers of differentiated large-sized lobular units and a lower proportion with immature ducts following menarche (P < 0.05). Numbers of small lobules and terminal end buds and mammary epithelial cell proliferation did not differ by diet. Expression of progesterone receptor was lower in immature lobules of soy-fed animals (P < 0.05). Our findings suggest that consumption of soy starting before menarche may result in modest effects consistent with a more differentiated breast phenotype in adulthood. Cancer Prev Res; 6(8); 832–42. ©2013 AACR.
Data from Microscopic and Early-Stage Ovarian Cancers in BRCA1/2 Mutation Carriers: Building a Model for Early BRCA-Associated Tumorigenesis
Authors: Yates Melinda S. , Meyer Larissa A. , Deavers Michael T. , Daniels Molly S. , Keeler Elizabeth R. , Mok Samuel C. , Gershenson David M. , Lu Karen H.
Published: March 2024

Abstract
Risk-reducing salpingo-oophorectomy (RRSO) is the cornerstone of ovarian cancer prevention in BRCA1/2 mutation carriers. Occult fallopian tube and ovarian cancers have been reported in a small percentage of BRCA1/2 mutation carriers undergoing RRSO. Here, we review our single-institution experience with RRSO in BRCA1/2 mutation carriers to characterize cases of microscopic cancers in these patients. At the time of RRSO, 7.9% of BRCA1 mutation carriers were diagnosed with microscopic fallopian tube or ovarian cancers and no cases were diagnosed in BRCA2 mutation carriers. The majority of the microscopic cancers include cases that were confined to the fallopian tubes, although there were also cases involving ovaries only or peritoneal washings only. This suggests that the site of origin may be in the ovary, fallopian tube, or peritoneum for BRCA-associated serous cancers. However, an analysis of early-stage (stages I and II) ovarian and fallopian tube cancers diagnosed in BRCA1/2 mutation carriers confirms that the ovary is a preferred site for tumor growth with 11 of 14 early-stage cancers having a dominant ovarian mass. Overall, these data suggest that cancer initiation may occur in the ovary, fallopian tube, or peritoneum, but tumor growth and progression are favored in the ovary. We present an updated model for BRCA1/2 mutation–associated ovarian and fallopian tube carcinogenesis, which may aid in identifying improved prevention strategies for high-risk women who delay or decline RRSO. Cancer Prev Res; 4(3); 463–70. ©2011 AACR.
Data from Diagnosing Lynch Syndrome: More Light at the End of the Tunnel
Authors: Burt Randall W.
Published: March 2024

Abstract
Since the recognition of Lynch syndrome, which confers a high risk of colorectal, uterine, and other cancers, approaches to its diagnosis have included a family history of associated cancers and web-based algorithms. Identification of causative genes now allows a precise diagnosis, thus focusing present efforts on who should have genetic testing. Testing for cancer tissue changes can determine who should have germline genetic testing. Indeed, such tumor testing is now generally recommended for all newly diagnosed colorectal cancer cases. As reported in this issue of the journal by Yurgelun and colleagues (beginning on page 574), large colorectal adenomatous polyps (≥10 mm) from patients with Lynch syndrome exhibit findings similar to those in Lynch syndrome colorectal cancer tissues. This finding indicates that testing larger adenomas in persons at a significant risk for Lynch syndrome can now determine the need for germline genetic testing. Although further study is needed for general application, the present study justifies large polyp testing in high-risk families when cancer tissue is unavailable, albeit negative polyp tissue would not rule out Lynch syndrome, as would negative cancer tissue. Cancer Prev Res; 5(4); 507–10. ©2012 AACR.
Data from Liver Fatty Acid-Binding Protein (L-Fabp) Modifies Intestinal Fatty Acid Composition and Adenoma Formation in ApcMin/+ Mice
Authors: Dharmarajan Sekhar , Newberry Elizabeth P. , Montenegro Grace , Nalbantoglu ILKe , Davis Victoria R. , Clanahan Michael J. , Blanc Valerie , Xie Yan , Luo Jianyang , Fleshman James W. , Kennedy Susan , Davidson Nicholas O.
Published: March 2024

Abstract
Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, implying a role for fatty acid metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acid-binding protein (L-Fabp), a dominant intestinal fatty acid-binding protein, regulates intestinal fatty acid trafficking and metabolism, and L-Fabp deletion attenuates diet-induced obesity. Here, we examined whether changes in intestinal fatty acid metabolism following L-Fabp deletion modify adenoma development in ApcMin/+ mice. Compound L-Fabp−/−ApcMin/+ mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated, and polyunsaturated fat. L-Fabp−/−ApcMin/+ mice displayed significant reductions in adenoma number and total polyp area compared with ApcMin/+controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp−/−ApcMin/+ mice exhibited reductions in cellular proliferation, high-grade dysplasia, and nuclear β-catenin translocation. Intestinal fatty acid content was increased in L-Fabp−/−ApcMin/+ mice, and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated fatty acid species with reduced saturated fatty acid species. L-Fabp−/−ApcMin/+ mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp−/−ApcMin/+ mice displayed significant reductions in mRNA abundance of nuclear hormone receptors involved in cellular proliferation and in enzymes involved in lipogenesis. These findings collectively implicate L-Fabp as an important genetic modifier of intestinal tumorigenesis, and identify fatty acid trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity, and intestinal tumor formation. Cancer Prev Res; 6(10); 1026–37. ©2013 AACR.
Data from Urinary Protein Biomarkers in the Early Detection of Lung Cancer
Authors: Nolen Brian M. , Lomakin Aleksey , Marrangoni Adele , Velikokhatnaya Liudmila , Prosser Denise , Lokshin Anna E.
Published: March 2024

Abstract
The early detection of lung cancer has the potential to greatly impact disease burden through the timely identification and treatment of affected individuals at a manageable stage of development. The insufficient specificity demonstrated by currently used screening and diagnostic techniques has led to intense investigation into biomarkers as diagnostic tools. Urine may represent a noninvasive alternative matrix for diagnostic biomarker development. We performed an analysis of 242 biomarkers in urines obtained from 83 patients with non–small cell lung carcinomas (NSCLC), 74 patients diagnosed with benign pulmonary conditions, and 77 healthy donors. A large number of significant alterations were observed between the NSCLC and control groups. A multivariate analysis identified a three-biomarker panel consisting of IGFBP-1, sIL-1Ra, CEACAM-1, which discriminated NSCLC from healthy controls with a sensitivity/specificity of 84/95 in an initial training set and 72/100 in an independent validation set. This panel performed well among multiple subtypes of NSCLC and early-stage disease but demonstrated only limited efficacy for the discrimination of NSCLC from benign controls and limited specificity for patients with several other cancers and tuberculosis. These findings demonstrate that urine biomarkers may provide screening and diagnostic properties which exceed those reported for serum biomarkers and approach a level necessary for further clinical development. Cancer Prev Res; 8(2); 111–9. ©2014 AACR.
Data from Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis
Authors: Seishima Ryo , Wada Takeyuki , Tsuchihashi Kenji , Okazaki Shogo , Yoshikawa Momoko , Oshima Hiroko , Oshima Masanobu , Sato Toshiro , Hasegawa Hirotoshi , Kitagawa Yuko , Goldenring James R. , Saya Hideyuki , Nagano Osamu
Published: March 2024

Abstract
Loss of parietal cells initiates the development of spasmolytic polypeptide–expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) that enhances the ability to defend against reactive oxygen species (ROS) in epithelial cells is expressed de novo in SPEM of K19-Wnt1/C2mE mice, a transgenic model of gastric tumorigenesis, and is required for the efficient development of SPEM and gastric tumor in these animals. The role of ROS and its downstream signaling in CD44-dependent gastric tumorigenesis has remained unknown, however. With the use of the K19-Wnt1/C2mE mouse, we now show that parietal cells in the inflamed stomach are highly sensitive to oxidative stress and manifest activation of p38MAPK signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38MAPK signaling, inhibited parietal cell loss and the subsequent gastric tumorigenesis. Our results indicate that signaling activated by oxidative stress in parietal cells plays a key role in CD44-dependent gastric tumorigenesis. Cancer Prev Res; 8(6); 492–501. ©2015 AACR.
Data from Molecular Imaging of Inflammation and Carcinogenesis
Authors: Ostrov David A. , Contag Christopher H.
Published: March 2024

Abstract
Development of imaging agents that can be used broadly for early detection of neoplasia at various tissue sites and at various stages of disease and that also can assess states of minimal residual disease would have tremendous utility in the diagnosis and management of cancer. In a series of articles culminating with a report in this issue of the journal (beginning on page 1536), Uddin and colleagues show their ability to systemically target the enzyme COX-2 with imaging probes that will serve as agents for early detection, risk assessment, prognosis, and intervention outcome measures. These probes will enable the detection and localization of regions of inflammation and a wide variety of premalignant lesions and cancers, with utility in monitoring the effects of cancer prevention and therapy. Cancer Prev Res; 4(10); 1523–6. ©2011 AACR.
Data from A Phase IIa Randomized, Double-Blind Trial of Erlotinib in Inhibiting Epidermal Growth Factor Receptor Signaling in Aberrant Crypt Foci of the Colorectum
Authors: Gillen Daniel L. , Meyskens Frank L. , Morgan Timothy R. , Zell Jason A. , Carroll Robert , Benya Richard , Chen Wen-Pin , Mo Allen , Tucker Chris , Bhattacharya Asmita , Huang Zhiliang , Arcilla Myra , Wong Vanessa , Chung Jinah , Gonzalez Rachel , Rodriguez Luz Maria , Szabo Eva , Rosenberg Daniel W. , Lipkin Steven M.
Published: March 2024

Abstract
Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.
Data from Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas
Authors: Giardina Charles , Nakanishi Masako , Khan Awaad , Kuratnik Anton , Xu Wanli , Brenner Bruce , Rosenberg Daniel W.
Published: March 2024

Abstract
One variable that may affect the ability of vitamin D to reduce colon cancer risk is the expression of its high-affinity receptor, VDR. Here, we show that vitamin D does not reduce tumor formation in ApcΔ14/+ mice and that VDR expression is lost in the majority of the colon tumor cells. The extent of VDR loss corresponded inversely to the level of β-catenin nuclear localization and could be observed in early lesions composed of just a few crypts. Analysis of reported VDR regulators showed that the repressing class I histone deacetylases (HDAC) were significantly elevated in the tumors (up to 4-fold), whereas the VDR-activating retinoid X receptors (RXR) were downregulated (∼50%). Expression of the Slug repressor was also increased, but was found primarily in stromal cells. Analysis of epigenetically active compounds on colon cell lines and intestinal organoids showed that HDAC inhibitors were particularly adept at stimulating VDR expression. Treatment of tumor-bearing ApcΔ14/+ mice with the HDAC inhibitor panobinostat increased VDR expression in the tumors and normal mucosa. The RXR agonist bexarotene failed to activate VDR expression, indicating that RXR ligands were not limiting. Analysis of human microarray data indicated that VDR mRNA is frequently downregulated in colon adenomas, which correlated positively with RXRA expression and inversely with HDAC 2 and 8 expression. Human adenomas showed variable VDR protein expression levels, both between and within individual lesions. Determining the mechanisms of VDR regulation in colon neoplasms may significantly enhance our ability to use vitamin D as a cancer prevention agent. Cancer Prev Res; 8(5); 387–99. ©2015 AACR.
Data from Fluorinated COX-2 Inhibitors as Agents in PET Imaging of Inflammation and Cancer
Authors: Uddin Md. Jashim , Crews Brenda C. , Ghebreselasie Kebreab , Huda Imran , Kingsley Philip J. , Ansari Mohammad Sib , Tantawy Mohammed N. , Reese Jeffery , Marnett Lawrence J.
Published: March 2024

Abstract
COX-2 is a major contributor to the inflammatory response and cancer progression so it is an important target for prevention and therapy. COX-2 is absent or expressed at low levels in most epithelial cells but is found at high levels in inflammatory lesions, and many premalignant and malignant tumors. Thus, it is an attractive target for molecular imaging. We report a series of novel fluorinated imaging agents, derived from indomethacin or celecoxib that selectively inhibit COX-2. The most promising lead, compound 7, was a fluorinated derivative of celecoxib. Kinetic analysis revealed that this fluorinated compound is a slow, tight-binding inhibitor of COX-2 and exhibits minimal inhibitory activity against COX-1. Efficient incorporation of 18F into compound 7 by radiochemical synthesis and intravenous injection provided sufficient signal for in vivo positron emission tomography (PET) imaging. Selective uptake of 18F-7 was observed in inflamed rat paws compared with the noninflamed contralateral paws and uptake was blocked by pretreatment with the COX-2 inhibitor, celecoxib. Uptake of 18F-7 was not observed when inflammation was induced in COX-2–null mice. In nude mice bearing both a COX-2–expressing human tumor xenograft (1483) and a COX-2–negative xenograft (HCT116), 18F-7 selectively accumulated in the COX-2–expressing tumor. Accumulation was blocked by pretreatment of the animals with celecoxib. The in vitro and in vivo properties of compound 7 suggest it will be a useful probe for early detection of cancer and for evaluation of the COX-2 status of premalignant and malignant tumors. Cancer Prev Res; 4(10); 1536–45. ©2011 AACR.
Data from Effect of Combined Treatment with Ursolic Acid and Resveratrol on Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate
Authors: Cho Jiyoon , Rho Okkyung , Junco Jacob , Carbajal Steve , Siegel Dionicio , Slaga Thomas J. , DiGiovanni John
Published: March 2024

Abstract
In this study, the effects of combining ursolic acid + resveratrol, for possible combined inhibitory effects on skin tumor promotion, were evaluated. Ursolic acid, resveratrol, and the combination of ursolic acid + resveratrol were applied topically prior to 12-O-tetracanoylphorbol-13-acetate (TPA) treatment on mouse skin to examine their effect on TPA-induced signaling pathways, epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion. The combination of ursolic acid + resveratrol produced a greater inhibition of TPA-induced epidermal hyperproliferation. The combination of ursolic acid + resveratrol inhibited TPA-induced signaling pathways, including EGFR, STAT3, Src, Akt, Cox-2, Fas, NF-κB, p38 MAPK, c-Jun, and JNK1/2 while increasing levels of tumor suppressors, such as p21 and PDCD4, to a greater extent compared with the groups treated with the individual compounds. Ursolic acid + resveratrol also induced a dramatic increase of p-AMPK-αThr172. Combined treatment with ursolic acid + resveratrol resulted in a greater inhibition of expression of proinflammatory cytokines, including Il1a, Il1b, and Il22. Furthermore, NF-κB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of ursolic acid + resveratrol. Treatment with ursolic acid + resveratrol during skin tumor promotion with TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the greater ability of the combination of ursolic acid + resveratrol to inhibit skin tumor promotion was due to the greater inhibitory effects on growth factor and inflammatory signaling, skin inflammation, and epidermal hyperproliferation induced by TPA treatment. Cancer Prev Res; 8(9); 817–25. ©2015 AACR.
Data from Plasma MicroRNAs as Novel Biomarkers for Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Permuth-Wey Jennifer , Chen Dung-Tsa , Fulp William J. , Yoder Sean J. , Zhang Yonghong , Georgeades Christina , Husain Kazim , Centeno Barbara Ann , Magliocco Anthony M. , Coppola Domenico , Malafa Mokenge
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers worldwide, partly because methods are lacking to detect disease at an early, operable stage. Noninvasive PDAC precursors called intraductal papillary mucinous neoplasms (IPMN) exist, and strategies are needed to aid in their proper diagnosis and management. Data support the importance of miRNAs in the progression of IPMNs to malignancy, and we hypothesized that miRNAs may be shed from IPMN tissues and detected in blood. Our primary goals were to measure the abundance of miRNAs in archived preoperative plasma from individuals with pathologically confirmed IPMNs and healthy controls and discover plasma miRNAs that distinguish between IPMN patients and controls and between “malignant” and “benign” IPMNs. Using novel nCounter technology to evaluate 800 miRNAs, we showed that a 30-miRNA signature distinguished 42 IPMN cases from 24 controls [area underneath the curve (AUC) = 74.4; 95% confidence interval (CI), 62.3–86.5, P = 0.002]. The signature contained novel miRNAs and miRNAs previously implicated in pancreatic carcinogenesis that had 2- to 4-fold higher expression in cases than controls. We also generated a 5-miRNA signature that discriminated between 21 malignant (high-grade dysplasia and invasive carcinoma) and 21 benign (low- and moderate-grade dysplasia) IPMNs (AUC = 73.2; 95% CI, 57.6–88.9, P = 0.005), and showed that paired plasma and tissue samples from patients with IPMNs can have distinct miRNA expression profiles. This study suggests feasibility of using new cost-effective technology to develop a miRNA-based blood test to aid in the preoperative identification of malignant IPMNs that warrant resection while sparing individuals with benign IPMNs the morbidity associated with overtreatment. Cancer Prev Res; 8(9); 826–34. ©2015 AACR.
Data from The Effects of Varying Dietary Carbohydrate and Fat Content on Survival in a Murine LNCaP Prostate Cancer Xenograft Model
Authors: Mavropoulos John C. , Buschemeyer W. Cooper , Tewari Alok K. , Rokhfeld Dmitriy , Pollak Michael , Zhao Yunhua , Febbo Phillip G. , Cohen Pinchas , Hwang David , Devi Gayathri , Demark-Wahnefried Wendy , Westman Eric C. , Peterson Bercedis L. , Pizzo Salvatore V. , Freedland Stephen J.
Published: March 2024

Abstract
Purpose: Numerous dietary factors elevate serum levels of insulin and insulin-like growth factor I (IGF-I), both potent prostate cancer mitogens. We tested whether varying dietary carbohydrate and fat, without energy restriction relative to comparison diets, would slow tumor growth and reduce serum insulin, IGF-I, and other molecular mediators of prostate cancer in a xenograft model.

Experimental Design: Individually caged male severe combined immunodeficient mice (n = 130) were randomly assigned to one of three diets (described as percent total calories): very high-fat/no-carbohydrate ketogenic diet (NCKD: 83% fat, 0% carbohydrate, 17% protein), low-fat/high-carbohydrate diet (LFD: 12% fat, 71% carbohydrate, 17% protein), or high-fat/moderate-carbohydrate diet (MCD: 40% fat, 43% carbohydrate, 17% protein). Mice were fed to maintain similar average body weights among groups. Following a preliminary feeding period, mice were injected with 1 × 106 LNCaP cells (day 0) and sacrificed when tumors were ≥1,000 mm3.

Results: Two days before tumor injection, median NCKD body weight was 2.4 g (10%) and 2.1 g (8%) greater than the LFD and MCD groups, respectively (P < 0.0001). Diet was significantly associated with overall survival (log-rank P = 0.004). Relative to MCD, survival was significantly prolonged for the LFD (hazard ratio, 0.49; 95% confidence interval, 0.29-0.79; P = 0.004) and NCKD groups (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.02). Median serum insulin, IGF-I, IGF-I/IGF binding protein-1 ratio, and IGF-I/IGF binding protein-3 ratio were significantly reduced in NCKD relative to MCD mice. Phospho-AKT/total AKT ratio and pathways associated with antiapoptosis, inflammation, insulin resistance, and obesity were also significantly reduced in NCKD relative to MCD tumors.

Conclusions: These results support further preclinical exploration of carbohydrate restriction in prostate cancer and possibly warrant pilot or feasibility testing in humans.