bluuebunny/crossref_metadata_2025 huggingface dataset:
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: April 2023

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 A Novel Molecular Pathway for Snail-Dependent, SPARC-Mediated Invasion in Non–Small Cell Lung Cancer Pathogenesis
Authors: Grant Jeanette L. , Fishbein Michael C. , Hong Long-Sheng , Krysan Kostyantyn , Minna John D. , Shay Jerry W. , Walser Tonya C. , Dubinett Steven M.
Published: April 2023

Abstract
Definition of the molecular pathogenesis of lung cancer allows investigators an enhanced understanding of the natural history of the disease, thus fostering development of new prevention strategies. In addition to regulating epithelial-to-mesenchymal transition (EMT), the transcription factor Snail exerts global effects on gene expression. Our recent studies reveal that Snail is upregulated in non–small cell lung cancer (NSCLC), is associated with poor prognosis, and promotes tumor progression in vivo. Herein, we demonstrate that overexpression of Snail leads to the upregulation of secreted protein, acidic and rich in cysteine (SPARC) in models of premalignancy and established disease, as well as in lung carcinoma tissues in situ. Snail overexpression leads to increased SPARC-dependent invasion in vitro, indicating that SPARC may play a role in lung cancer progression. Bioinformatic analysis implicates transforming growth factor beta (TGF-β), extracellular signal–regulated kinase (ERK)1/2, and miR-29b as potential intermediaries in Snail-mediated upregulation of SPARC. Both the TGF-β1 ligand and TGF-β receptor 2 (TGF-βR2) are upregulated following Snail overexpression. Treatment of human bronchial epithelial cell (HBEC) lines with TGF-β1 and inhibition of TGF-β1 mRNA expression modulates SPARC expression. Inhibition of MAP–ERK kinase (MEK) phosphorylation downregulates SPARC. MiR-29b is downregulated in Snail-overexpressing cell lines, whereas overexpression of miR-29b inhibits SPARC expression. In addition, miR-29b is upregulated following ERK inhibition, suggesting a Snail-dependent pathway by which Snail activation of TGF-β and ERK signaling results in downregulation of miR-29b and subsequent upregulation of SPARC. Our discovery of pathways responsible for Snail-induced SPARC expression contributes to the definition of NSCLC pathogenesis. Cancer Prev Res; 7(1); 150–60. ©2013 AACR.
Data from Oral Contraceptives Decrease the Prevalence of Ovarian Cancer in the Hen
Authors: Treviño Lindsey S. , Buckles Elizabeth L. , Johnson Patricia A.
Published: April 2023

Abstract
Ovarian cancer is the leading cause of reproductive cancer death in U.S. women. This high mortality rate is due to the lack of early detection methods and ineffectiveness of therapy for advanced disease. Until more effective screening methods and therapies are developed, chemoprevention strategies are warranted. The hen has a high spontaneous prevalence of ovarian cancer and has been used as a model for studying ovarian cancer chemoprevention. In this study, we used the hen to determine the effect of progestin alone, estrogen alone, or progestin and estrogen in combination (as found in oral contraceptives) on ovarian cancer prevalence. We found that treatment with progestin alone and in combination with estrogen decreased the prevalence of ovarian cancer. A significant risk reduction of 91% was observed in the group treated with progestin alone (risk ratio = 0.0909; 95% CI: 0.0117–0.704) and an 81% reduction was observed in the group treated with progestin plus estrogen (risk ratio = 0.1916; 95% CI = 0.043–0.864). Egg production was also significantly reduced in these treatment groups compared with control. We found no effect of progestin, either alone or in combination with estrogen, on apoptosis or proliferation in the ovary, indicating that this is not the likely mechanism responsible for the protective effect of progestin in the hen. Our results support the use of oral contraceptives to prevent ovarian cancer and suggest that ovulation is related to the risk of ovarian cancer in hens and that other factors, such as hormones, more than likely modify this risk. Cancer Prev Res; 5(2); 343–9. ©2011 AACR.
Data from Impact of Screening Test Performance and Cost on Mortality Reduction and Cost-effectiveness of Multimodal Ovarian Cancer Screening
Authors: Drescher Charles W. , Hawley Sarah , Thorpe Jason D. , Marticke Simone , McIntosh Martin , Gambhir Sanjiv S. , Urban Nicole
Published: April 2023

Abstract
Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests [CA125 and transvaginal sonography (TVS)]. Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current limits. This study estimates the mortality reduction, years of life saved, and cost-effectiveness achievable by annual multimodal screening using increasing CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counterparts with better performance characteristics. An existing stochastic microsimulation model is refined and used to screen a virtual cohort of 1 million women from ages 45 to 85 years. Each woman is assigned a detailed disease course and screening results timeline. The preclinical behavior of CA125 and TVS is simulated using empirical data derived from clinical trials. Simulations in which the disease incidence and performance characteristics of the screening tests are independently varied are conducted to evaluate the impact of these factors on overall screening performance and costs. Our results show that when applied to women at average risk, annual screening using increasing CA125 to select women for TVS achieves modest mortality reduction (∼13%) and meets currently accepted cost-effectiveness guidelines. Screening outcomes are relatively insensitive to second-line test performance and costs. Identification of a first-line test that does substantially better than CA125 and has similar costs is required for screening to reduce ovarian mortality by at least 25% and be reasonably cost-effective. Cancer Prev Res; 5(8); 1015–24. ©2012 AACR.
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: April 2023

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 Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A “New” Biology of Estrogen-induced Apoptosis
Authors: Jordan V. Craig , Ford Leslie G.
Published: April 2023

Abstract
Administration of estrogen replacement therapy (ERT) decreases the incidence of breast cancer, as shown in a double-blind, placebo-controlled randomized trial of the Women's Health Initiative (WHI) in 10,739 postmenopausal women with a prior hysterectomy. Although paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances. Long-term antiestrogen treatment or estrogen deprivation causes the eventual development and evolution of antihormone resistance. Cell populations emerge with a vulnerability, as estrogen is no longer a survival signal but is an apoptotic trigger. The antitumor effect of ERT in estrogen-deprived postmenopausal women is consistent with laboratory models. Cancer Prev Res; 4(5); 633–7. ©2011 AACR.
Data from Stem Cell Antigen-1 Deficiency Enhances the Chemopreventive Effect of Peroxisome Proliferator–Activated Receptorγ Activation
Authors: Yuan Hongyan , Upadhyay Geeta , Yin Yuzhi , Kopelovich Levy , Glazer Robert I.
Published: April 2023

Abstract
Stem cell antigen-1 (Sca-1, Ly6A) is a glycerophosphatidylinositol (GPI)-anchored protein that was identified as a murine marker of bone marrow stem cells. Although Sca-1 is widely used to enrich for stem and progenitor cells in various tissues, little is known about its function and associated signaling pathways in normal and malignant cells. Here, we report that the absence of Sca-1 in the mammary gland resulted in higher levels of PPARγ and PTEN, and a reduction of pSer84PPARγ, pERK1/2, and PPARδ. This phenotype correlated with markedly increased sensitivity of Sca-1 null mice to PPARγ agonist GW7845 and insensitivity to PPARδ agonist GW501516. Reduction of Sca-1 expression in mammary tumor cells by RNA interference resulted in a phenotype similar to the Sca-1 deficient mammary gland, as evidenced by increased PPARγ expression and transcriptional activity, resulting in part from a lesser susceptibility to proteasomal degradation. These data implicate Sca-1 as a negative regulator of the tumor suppressor effects of PPARγ. Cancer Prev Res; 5(1); 51–60. ©2011 AACR.
Data from The Human Gut Microbiome as a Screening Tool for Colorectal Cancer
Authors: Zackular Joseph P. , Rogers Mary A.M. , Ruffin Mack T. , Schloss Patrick D.
Published: April 2023

Abstract
Recent studies have suggested that the gut microbiome may be an important factor in the development of colorectal cancer. Abnormalities in the gut microbiome have been reported in patients with colorectal cancer; however, this microbial community has not been explored as a potential screen for early-stage disease. We characterized the gut microbiome in patients from three clinical groups representing the stages of colorectal cancer development: healthy, adenoma, and carcinoma. Analysis of the gut microbiome from stool samples revealed both an enrichment and depletion of several bacterial populations associated with adenomas and carcinomas. Combined with known clinical risk factors of colorectal cancer (e.g., BMI, age, race), data from the gut microbiome significantly improved the ability to differentiate between healthy, adenoma, and carcinoma clinical groups relative to risk factors alone. Using Bayesian methods, we determined that using gut microbiome data as a screening tool improved the pretest to posttest probability of adenoma more than 50-fold. For example, the pretest probability in a 65-year-old was 0.17% and, after using the microbiome data, this increased to 10.67% (1 in 9 chance of having an adenoma). Taken together, the results of our study demonstrate the feasibility of using the composition of the gut microbiome to detect the presence of precancerous and cancerous lesions. Furthermore, these results support the need for more cross-sectional studies with diverse populations and linkage to other stool markers, dietary data, and personal health information. Cancer Prev Res; 7(11); 1112–21. ©2014 AACR.
Data from Lack of ABCG2 Shortens Latency of BRCA1-Deficient Mammary Tumors and This Is Not Affected by Genistein or Resveratrol
Authors: Zander Serge A.L. , Kersbergen Ariena , Sol Wendy , Gonggrijp Maaike , van de Wetering Koen , Jonkers Jos , Borst Piet , Rottenberg Sven
Published: April 2023

Abstract
In addition to their role in drug resistance, the ATP-binding cassette (ABC) transporters ABCG2 and ABCB1 have been suggested to protect cells from a broad range of substances that may foster tumorigenesis. Phytoestrogens or their metabolites are substrates of these transporters and the influence of these compounds on breast cancer development is controversial. Estrogen-like properties might accelerate tumorigenesis on the one hand, whereas their proposed health-protective properties might antagonize tumorigenesis on the other. To address this issue, we used a newer generation mouse model of BRCA1-mutated breast cancer and examined tumor latency in K14cre;Brca1F/F; p53F/F, Abcb1a/b−/−;K14cre;Brca1F/F; p53F/F, or Abcg2−/−;K14cre;Brca1F/F; p53F/F animals, fed with genistein- or resveratrol-supplemented diets. Ovariectomized K14cre;Brca1F/F; p53F/F animals were included to evaluate whether any estrogen-mimicking effects can restore mammary tumor development in the absence of endogenous estrogens. Compared with the ABC transporter proficient model, ABCG2-deficient animals showed a reduced median tumor latency of 17.5 days (P < 0.001), whereas no significant difference was observed for ABCB1-deficient animals. Neither genistein nor resveratrol altered this latency reduction in Abcg2−/−;K14cre;Brca1F/F; p53F/F animals. Ovariectomy resulted in nearly complete loss of mammary tumor development, which was not restored by genistein or resveratrol. Our results show that ABCG2 contributes to the protection of genetically instable epithelial cells against carcinogenesis. Diets containing high levels of genistein or resveratrol had no effect on mammary tumorigenesis, whether mice were lacking ABCG2 or not. Because genistein and resveratrol only delayed skin tumor development of ovariectomized animals, we conclude that these phytoestrogens are no effective modulators of mammary tumor development in our mouse model. Cancer Prev Res; 5(8); 1053–60. ©2012 AACR.
Data from Effects of Cigarette Smoke on the Human Oral Mucosal Transcriptome
Authors: Boyle Jay O. , Gümüş Zeynep H. , Kacker Ashutosh , Choksi Vishal L. , Bocker Jennifer M. , Zhou Xi Kathy , Yantiss Rhonda K. , Hughes Duncan B. , Du Baoheng , Judson Benjamin L. , Subbaramaiah Kotha , Dannenberg Andrew J.
Published: April 2023

Abstract
Use of tobacco is responsible for ∼30% of all cancer-related deaths in the United States, including cancers of the upper aerodigestive tract. In the current study, 40 current and 40 age- and gender-matched never smokers underwent buccal biopsies to evaluate the effects of smoking on the transcriptome. Microarray analyses were carried out using Affymetrix HGU133 Plus 2 arrays. Smoking altered the expression of numerous genes: 32 genes showed increased expression and 9 genes showed reduced expression in the oral mucosa of smokers versus never smokers. Increases were found in genes involved in xenobiotic metabolism, oxidant stress, eicosanoid synthesis, nicotine signaling, and cell adhesion. Increased numbers of Langerhans cells were found in the oral mucosa of smokers. Interestingly, smoking caused greater induction of aldo-keto reductases, enzymes linked to polycyclic aromatic hydrocarbon–induced genotoxicity, in the oral mucosa of women than men. Striking similarities in expression changes were found in oral compared with the bronchial mucosa. The observed changes in gene expression were compared with known chemical signatures using the Connectivity Map database and suggested that geldanamycin, a heat shock protein 90 inhibitor, might be an antimimetic of tobacco smoke. Consistent with this prediction, geldanamycin caused dose-dependent suppression of tobacco smoke extract–mediated induction of CYP1A1 and CYP1B1 in vitro. Collectively, these results provide new insights into the carcinogenic effects of tobacco smoke, support the potential use of oral epithelium as a surrogate tissue in future lung cancer chemoprevention trials, and illustrate the potential of computational biology to identify chemopreventive agents. Cancer Prev Res; 3(3); 266–78
Data from Beta-Endorphin Cell Therapy for Cancer Prevention
Authors: Zhang Changqing , Murugan Sengottuvelan , Boyadjieva Nadka , Jabbar Shaima , Shrivastava Pallavi , Sarkar Dipak K.
Published: April 2023

Abstract
β-Endorphin (BEP)–producing neuron in the hypothalamus plays a key role in bringing the stress axis to a state of homeostasis and maintaining body immune defense system. Long-term delivery of BEP to obtain beneficial effect on chemoprevention is challenging, as the peptides rapidly develop tolerance. Using rats as animal models, we show here that transplantation of BEP neurons into the hypothalamus suppressed carcinogens- and hormone-induced cancers in various tissues and prevented growth and metastasis of established tumors via activation of innate immune functions. In addition, we show that intracerebroventricular administration of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) increased the number of BEP neurons in the hypothalamus, reduced the stress response, enhanced the innate immune function, and prevented tumor cell growth, progression, and metastasis. BEP neuronal supplementation did not produce any deleterious effects on general health but was beneficial in suppressing age-induced alterations in physical activity, metabolic, and immune functions. We conclude that the neuroimmune system has significant control over cancer growth and progression, and that activation of the neuroimmune system via BEP neuronal supplementation/induction may have therapeutic value for cancer prevention and improvement of general health. Cancer Prev Res; 8(1); 56–67. ©2014 AACR.
Data from 17β-Estradiol and Tamoxifen Prevent Gastric Cancer by Modulating Leukocyte Recruitment and Oncogenic Pathways in Helicobacter Pylori–Infected INS-GAS Male Mice
Authors: Sheh Alexander , Ge Zhongming , Parry Nicola M.A. , Muthupalani Sureshkumar , Rager Julia E. , Raczynski Arkadiusz R. , Mobley Melissa W. , McCabe Amanda F. , Fry Rebecca C. , Wang Timothy C. , Fox James G.
Published: April 2023

Abstract
Helicobacter pylori infection promotes male predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies showed that prophylactic 17β-estradiol (E2) in INS-GAS mice decreases H. pylori–induced carcinogenesis. We examined the effect of E2 and tamoxifen (TAM) on H. pylori–induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks postinfection (WPI), mice were implanted with E2, TAM, both E2 and TAM, or placebo pellets for 12 weeks. At 28 WPI, gastric histopathology, gene expression, and immune cell infiltration were evaluated and serum inflammatory cytokines measured. After treatment, no gastric cancer was observed in H. pylori–infected males receiving E2 and/or TAM, whereas 40% of infected untreated males developed gastric cancer. E2, TAM, and their combination significantly reduced gastric precancerous lesions in infected males compared with infected untreated males (P < 0.001, 0.01, and 0.01, respectively). However, TAM did not alter female pathology regardless of infection status. Differentially expressed genes from males treated with E2 or TAM (n = 363 and n = 144, Q < 0.05) associated highly with cancer and cellular movement, indicating overlapping pathways in the reduction of gastric lesions. E2 or TAM deregulated genes associated with metastasis (PLAUR and MMP10) and Wnt inhibition (FZD6 and SFRP2). Compared with controls, E2 decreased gastric mRNA (Q < 0.05) and serum levels (P < 0.05) of CXCL1, a neutrophil chemokine, leading to decreased neutrophil infiltration (P < 0.01). Prevention of H. pylori–induced gastric cancer by E2 and TAM may be mediated by estrogen signaling and is associated with decreased CXCL1, decreased neutrophil counts, and downregulation of oncogenic pathways. Cancer Prev Res; 4(9); 1426–35. ©2011 AACR.
Data from Metformin Prevents Tobacco Carcinogen–Induced Lung Tumorigenesis
Authors: Memmott Regan M. , Mercado Jose R. , Maier Colleen R. , Kawabata Shigeru , Fox Stephen D. , Dennis Phillip A.
Published: April 2023

Abstract
Activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen–induced lung tumorigenesis, and therapies that target mTOR could be effective in the prevention or treatment of lung cancer. The biguanide metformin, which is widely prescribed for the treatment of type II diabetes, might be a good candidate for lung cancer chemoprevention because it activates AMP-activated protein kinase (AMPK), which can inhibit the mTOR pathway. To test this, A/J mice were treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that are achievable in humans. mTOR was inhibited in lung tumors but only modestly. To test whether intraperitoneal administration of metformin might improve mTOR inhibition, we injected mice and assessed biomarkers in liver and lung tissues. Plasma levels of metformin were significantly higher after injection than oral administration. In liver tissue, metformin activated AMPK and inhibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal–regulated kinase (ERK), and mTOR. This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. Based on these data, we repeated the NNK–induced lung tumorigenesis study using intraperitoneal administration of metformin. Metformin decreased tumor burden by 72%, which correlated with decreased cellular proliferation and marked inhibition of mTOR in tumors. These studies show that metformin prevents tobacco carcinogen–induced lung tumorigenesis and support clinical testing of metformin as a chemopreventive agent. Cancer Prev Res; 3(9); 1066–76. ©2010 AACR.
Data from A Multiantigen Vaccine Targeting Neu, IGFBP-2, and IGF-IR Prevents Tumor Progression in Mice with Preinvasive Breast Disease
Authors: Disis Mary L. , Gad Ekram , Herendeen Daniel R. , Lai Vy Phan- , Park Kyong Hwa , Cecil Denise L. , O'Meara Megan M. , Treuting Piper M. , Lubet Ronald A.
Published: April 2023

Abstract
A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4+ T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin—like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4+ T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8+ T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P < 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease. Cancer Prev Res; 6(12); 1273–82. ©2013 AACR.
Data from Examining Stools for Colon Cancer Prevention: What Are We Really Looking for?
Authors: Byers Tim
Published: April 2023

Abstract
Fecal immunochemical testing (FIT) is superior to guiac-based testing if we are looking for blood in stools, as it has better one-time colorectal cancer sensitivity and specificity and better patient acceptance. In this issue of the journal, Cai and colleagues (beginning on page 1572) and Khalid-de Bakker and colleagues (beginning on page 1563) present new information about the one-time test performance of FIT. FIT will have a growing appeal to providers and health care systems as resources for clinical preventive services shrink and as incentives to expand colorectal screening rates increase, but there are good reasons to be cautious about the temptation to organize new FIT screening programs. Colorectal screening has two potential objectives: To find cancers in an earlier, more-treatable stage and to find and remove adenomas to prevent cancers from forming in the first place. Because most adenomas, even advanced adenomas, do not bleed, tests designed to identify occult blood in the stool are better for detecting colorectal cancer, whereas direct endoscopic visualization of the colorectum is better for prevention. Even if advanced adenomas did commonly bleed, low compliance with repeat annual testing will seriously erode the benefit of FIT. Cancer Prev Res; 4(10); 1531–3. ©2011 AACR.
Data from Curcumin Modulates MicroRNA-203–Mediated Regulation of the Src-Akt Axis in Bladder Cancer
Authors: Saini Sharanjot , Arora Sumit , Majid Shahana , Shahryari Varahram , Chen Yi , Deng Guoren , Yamamura Soichiro , Ueno Koji , Dahiya Rajvir
Published: April 2023

Abstract
Bladder cancer is often associated with recurrence and progression to invasive metastatic disease that have palliative therapeutic options. The use of traditional chemotherapeutic agents for bladder cancer management often suffers from toxicity and resistance concerns. This emphasizes the need for development of safer, natural, nontoxic compounds as chemotherapeutic/chemopreventive agents. Curcumin (diferuloylmethane) is a natural compound that has been known to possess anticancer properties in various cancers, including bladder cancer. However, the biological targets of curcumin are not well defined. Recently, it has been proposed that curcumin may mediate epigenetic modulation of expression of microRNAs (miRNA). In this article, we define for the first time, that curcumin directly induces a tumor-suppressive miRNA, miR-203, in bladder cancer. miR-203 is frequently downregulated in bladder cancer due to DNA hypermethylation of its promoter. We studied the functional significance of miR-203 in bladder cancer cell lines and found that miR-203 has tumor suppressive properties. Also, we define Akt2 and Src as novel miR-203 targets in bladder cancer. Curcumin induces hypomethylation of the miR-203 promoter and subsequent upregulation of miR-203 expression. This leads to downregulation of miR-203 target genes Akt2 and Src that culminates in decreased proliferation and increased apoptosis of bladder cancer cells. This is the first report that shows a direct effect of curcumin on inducing epigenetic changes at a miRNA promoter with direct biological consequences. Our study suggests that curcumin may offer a therapeutic advantage in the clinical management of refractory bladder cancer over other standard treatment modalities. Cancer Prev Res; 4(10); 1698–709. ©2011 AACR.
Data from Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study
Authors: Moreira Daniel M. , Nickel J. Curtis , Gerber Leah , Muller Roberto L. , Andriole Gerald L. , Castro-Santamaria Ramiro , Freedland Stephen J.
Published: April 2023

Abstract
Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations. Cancer Prev Res; 8(4); 312–7. ©2015 AACR.
Data from Performance of a Colorectal Cancer Screening Protocol in an Economically and Medically Underserved Population
Authors: Cai Shan-Rong , Zhang Su-Zhan , Zhu Hong-Hong , Huang Yan-Qin , Li Qi-Rong , Ma Xin-Yuan , Yao Kai-Yan , Zheng Shu
Published: April 2023

Abstract
The performance of combining fecal immunochemical tests (FITs) and a high-risk factor questionnaire (HRFQ) in colorectal cancer (CRC) screening in economically and medically underserved populations is uncertain. This study investigated the performance of a CRC screening protocol of combining FITs and an HRFQ as primary screening methods in a rural Chinese population. A CRC mass screening was conducted using FITs and an HRFQ as the first and colonoscopy as the second stage of screening in Jiashan, 2007–2009. The target population was 31,963 residents in three communities. The compliance was 84.7% for HRFQ, 76.4% for FITs, and 78.7% for colonoscopy. The detected rates of cancer, adenoma, nonadenomatous polyps, and advanced neoplasm were 2.7%, 14.8%, 5.9%, and 8.9% by FITs, which were higher than those by HRFQ (0.5%, 9.2%, 4.8%, and 3.8%, respectively). There was no significant difference in detected rate for nonadenomatous polyps between FITs and HRFQ. A total of 41.2% adenomas, 53.2% nonadenomatous polyps, and 29.8% advanced neoplasms were detected by HRFQ but missed by FITs. Positive predictive value of the screening protocol of combining FITs and HRFQ for advanced neoplasm was 5.7%, which was higher than FITs alone. Men had a higher prevalence of advanced neoplasm than women. Results indicate that combining FITs and HRFQ as primary screening methods is an efficient CRC screening strategy in economically and medically underserved populations. Cancer Prev Res; 4(10); 1572–9. ©2011 AACR.
Data from Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus
Authors: Li Xiaohong , Paulson Thomas G. , Galipeau Patricia C. , Sanchez Carissa A. , Liu Karen , Kuhner Mary K. , Maley Carlo C. , Self Steven G. , Vaughan Thomas L. , Reid Brian J. , Blount Patricia L.
Published: April 2023

Abstract
Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case–cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution. Cancer Prev Res; 8(9); 845–56. ©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: April 2023

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 St. John's Wort Attenuates Colorectal Carcinogenesis in Mice through Suppression of Inflammatory Signaling
Authors: Manna Soumen K. , Golla Srujana , Golla Jaya Prakash , Tanaka Naoki , Cai Yan , Takahashi Shogo , Krausz Kristopher W. , Matsubara Tsutomu , Korboukh Ilia , Gonzalez Frank J.
Published: April 2023

Abstract
Despite widespread use as well as epidemiologic indications, there have been no investigations into the effect of St. John's wort (SJW) extract on colorectal carcinogenesis in vivo. This study reports a systematic evaluation of the impact of dietary supplementation of SJW extract on azoxymethane-induced colorectal carcinogenesis in mice. Mice were fed with either AIN-93G (control) diet or SJW extract–supplemented diet (SJW diet) prior to azoxymethane treatment. SJW diet was found to significantly improve the overall survival of azoxymethane-treated mice. Pretreatment with the SJW diet significantly reduced body weight loss as well as decrease of serum albumin and cholesterol levels associated with azoxymethane-induced colorectal tumorigenesis. SJW diet–fed mice showed a significant decrease in tumor multiplicity along with a decrease in incidence of large tumors and a trend toward decreased total tumor volume in a dose-dependent manner. A short-term study, which examined the effect of SJW prior to rectal bleeding, also showed decrease in colorectal polyps in SJW diet–fed mice. Nuclear factor kappa B (NF-κB) and extracellular signal–regulated kinase (ERK1/2) pathways were attenuated by SJW administration. SJW extract resulted in early and continuous attenuation of these pathways in the colon epithelium of SJW diet–fed mice under both short-term and long-term treatment regimens. In conclusion, this study demonstrated the chemopreventive potential of SJW extract against colorectal cancer through attenuation of proinflammatory processes. Cancer Prev Res; 8(9); 786–95. ©2015 AACR.
Data from A Gene Expression Signature from Peripheral Whole Blood for Stage I Lung Adenocarcinoma
Authors: Rotunno Melissa , Hu Nan , Su Hua , Wang Chaoyu , Goldstein Alisa M. , Bergen Andrew W. , Consonni Dario , Pesatori Angela C. , Bertazzi Pier Alberto , Wacholder Sholom , Shih Joanna , Caporaso Neil E. , Taylor Phil R. , Landi Maria Teresa
Published: April 2023

Abstract
Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology study using PWB and paired snap-frozen tumor and noninvolved lung tissue samples. Analyses were conducted using unpaired t tests, linear mixed effects, and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (false discovery rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus noninvolved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer–related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case–control study (n = 212) and a tumor–nontumor paired tissue study (n = 54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC = 0.81, 95% CI = 0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future. Cancer Prev Res; 4(10); 1599–608. ©2011 AACR.
Data from Effect of Metformin, Rapamycin, and Their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice
Authors: Saha Achinto , Blando Jorge , Tremmel Lisa , DiGiovanni John
Published: April 2023

Abstract
In this study, we compared the effect of oral administration of metformin (MET) and rapamycin (RAPA) alone or in combination on prostate cancer development and progression in HiMyc mice. MET (250 mg/kg body weight in the drinking water), RAPA (2.24 mg/kg body weight microencapsulated in the diet), and the combination inhibited progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate (VP). RAPA and the combination were more effective than MET at the doses used. Inhibition of prostate cancer progression in HiMyc mice by RAPA was associated with a significant reduction in mTORC1 signaling that was further potentiated by the combination of MET and RAPA. In contrast, treatment with MET alone enhanced AMPK activation, but had little or no effect on mTORC1 signaling pathways in the VP of HiMyc mice. Further analyses revealed a significant effect of all treatments on prostate tissue inflammation as assessed by analysis of the expression of cytokines, the presence of inflammatory cells and NFκB signaling. MET at the dose used appeared to reduce prostate cancer progression primarily by reducing tissue inflammation whereas RAPA and the combination appeared to inhibit prostate cancer progression in this mouse model via the combined effects on both mTORC1 signaling as well as on tissue inflammation. Overall, these data support the hypothesis that blocking mTORC1 signaling and/or tissue inflammation can effectively inhibit prostate cancer progression in a relevant mouse model of human prostate cancer. Furthermore, combinatorial approaches that target both pathways may be highly effective for prevention of prostate cancer progression in men. Cancer Prev Res; 8(7); 597–606. ©2015 AACR.
Data from Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Premenopausal Women
Authors: Fabian Carol J. , Kimler Bruce F. , Phillips Teresa A. , Box Jessica A. , Kreutzjans Amy L. , Carlson Susan E. , Hidaka Brandon H. , Metheny Trina , Zalles Carola M. , Mills Gordon B. , Powers Kandy R. , Sullivan Debra K. , Petroff Brian K. , Hensing Whitney L. , Fridley Brooke L. , Hursting Stephen D.
Published: April 2023

Abstract
Higher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore the effects of high-dose EPA and DHA on blood and benign breast tissue risk biomarkers before design of a placebo-controlled phase IIB trial. Premenopausal women with evidence of hyperplasia ± atypia by baseline random periareolar fine needle aspiration were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase prestudy and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility, which was predefined as 50% uptake, 85% retention, and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77% to 38% (P = 0.002), and Ki-67 from a median of 2.1% to 1.0% (P = 0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo-controlled trial in premenopausal women is warranted. Cancer Prev Res; 8(10); 912–21. ©2015 AACR.

See related article, p. 922.