bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Red Wine Consumption is Inversely Associated with 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine–DNA Adduct Levels in Prostate
Authors: Rybicki Benjamin A. , Neslund-Dudas Christine , Bock Cathryn H. , Nock Nora L. , Rundle Andrew , Jankowski Michelle , Levin Albert M. , Beebe-Dimmer Jennifer , Savera Adnan T. , Takahashi Satoru , Shirai Tomoyuki , Tang Deliang
Published: April 2023

Abstract
In humans, genetic variation and dietary factors may alter the biological effects of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the major heterocyclic amines generated from cooking meats at high temperatures that has carcinogenic potential through the formation of DNA adducts. Previously, we reported grilled red meat consumption associated with PhIP–DNA adduct levels in human prostate. In this study, we expanded our investigation to estimate the associations between beverage consumption and PhIP–DNA adduct levels in prostate for 391 prostate cancer cases. Of the 15 beverages analyzed, red wine consumption had the strongest association with PhIP–DNA adduct levels showing an inverse correlation in both tumor (P = 0.006) and nontumor (P = 0.002) prostate cells. Red wine consumption was significantly lower in African American compared with white cases, but PhIP–DNA adduct levels in prostate did not vary by race. In African Americans compared with whites, however, associations between red wine consumption and PhIP–DNA adduct levels were not as strong as associations with specific (e.g., SULT1A1 and UGT1A10 genotypes) and nonspecific (e.g., African ancestry) genetic variation. In a multivariable model, the covariate for red wine consumption explained a comparable percentage (13%–16%) of the variation in PhIP–DNA adduct levels in prostate across the two racial groups, but the aforementioned genetic factors explained 33% of the PhIP–DNA adduct variation in African American cases, whereas only 19% of the PhIP–DNA adduct variation in whites. We conclude that red wine consumption may counteract biological effects of PhIP exposure in human prostate, but genetic factors may play an even larger role, particularly in African Americans. Cancer Prev Res; 4(10); 1636–44. ©2011 AACR.
Data from Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
Authors: Ren Xian-Yue , Zhou Guan-Qun , Jiang Wei , Sun Ying , Xu Ya-Fei , Li Ying-Qin , Tang Xin-Ran , Wen Xin , He Qing-Mei , Yang Xiao-Jing , Liu Na , Ma Jun
Published: April 2023

Abstract
Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/β-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36–3.94; P = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23–3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19–3.59; P = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. β-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. Cancer Prev Res; 8(10); 968–77. ©2015 AACR.
Data from Chemoprevention of Colon Cancer in a Rat Carcinogenesis Model Using a Novel Nanotechnology-Based Combined Treatment System
Authors: Chaudhary Abhishek , Sutaria Dhruvitkumar , Huang Ying , Wang Jeffrey , Prabhu Sunil
Published: April 2023

Abstract
Colorectal cancer (CRC) is the third most common cause of cancer death in the United States, accounting for approximately 51,000 deaths each year. We have previously shown in vitro chemopreventive effects of mixtures of aspirin, folic acid, and calcium (AFAC) on colon cancer cell lines. The objective of the present study was to evaluate the in vivo effects of orally administered, colon targeted chemopreventive combination regimens on the inhibition of aberrant crypt foci (ACF) in a rat model of colon carcinogenesis using (i) unmodified (free drug) combinations of AFAC and (ii) nanoparticle-encapsulated combinations of the same agents. A 14-week animal study was conducted in three phases to determine an optimal effective dose from AFAC combinations and evaluate the efficacy of nanotechnology-based chemopreventive regimens administered in combined (mixtures) and individual (single entity) forms. ACF inhibition when compared with azoxymethane-treated rat control group was significant in both the unmodified and the modified nanoparticle-mediated chemopreventive regimens, showing a range of 31% to 38% (P < 0.05) and 50% to 75% (P < 0.001) reduction, respectively, in the number of ACFs. In addition, the nanoparticulate combination regimens of AFAC showed a 2-fold increase in suppression of ACF compared with free drug mixtures. Individual administration of nanoparticle-encapsulated drugs showed no significant effect on the reduction of ACF. Histochemical analysis provided further confirmation of chemopreventive effects, showing a significant reduction in cell nuclear proliferation. Overall, our results provide a strong proof of concept using nanoparticle-mediated combination treatment in the chemoprevention of colon cancer. Cancer Prev Res; 4(10); 1655–64. ©2011 AACR.
Data from Alcohol-metabolizing Enzymes' Gene Polymorphisms and Susceptibility to Multiple Head and Neck Cancers
Authors: Chien Huei-Tzu , Young Chi-Kuang , Chen Tzu-Ping , Liao Chun-Ta , Wang Hung-Ming , Cheng Sou-De , Huang Shiang-Fu
Published: April 2023

Abstract
Multiple primary tumors (MPT), especially in the hypopharynx and esophagus, are challenging in patients with head and neck cancer (HNC). Alcohol and alcohol-metabolizing genes were reported to be related to upper digestive tract cancers. Here, we investigated whether the genotypes of alcohol-metabolizing enzymes (ADH1B, ADH1C, and ALDH2) affected patients' susceptibility to developing MPTs. We recruited 659 male patients with HNC between March 1996 and February 2017. Age- and gender-matched controls were also recruited. A total of 164 patients with HNC were identified to have second or third malignancies. The single-nucleotide polymorphisms in ADH1B (rs1229984), ADH1C (rs698), and ALDH2 (rs671) were analyzed by TaqMan assays. The prevalence of ALDH2 *2 allele carriers is significantly higher than that of *1*1 homozygotes for oral cavity (P = 0.013) and oropharyngeal cancers (P = 0.012). For ADH1B, the number of *1 allele carriers is significantly higher than that of *2*2 homozygotes for oropharyngeal (P = 0.017) and hypopharyngeal cancers (P < 0.001). ADH1C (rs698) SNPs are not significantly associated with tumor subsites (all P > 0.05). Polymorphisms in ALDH2 (*2 allele carriers) and ADH1B (*1 allele carriers) significantly increase the risk of developing MPTs in the upper digestive tract [P < 0.001, OR (95% confidence interval (CI): 5.186 (2.444–11.004) and P < 0.05, OR (95% CI): 2.093 (1.149–3.812), respectively]. ALDH2 (rs671) *2 and ADH1B (rs1229984) *1 allele carriers were shown to develop MPTs in the upper digestive tract. Genetic information may be used to identify high-risk patients for the development of MPTs.
Data from Prevention of Lipid Peroxidation–derived Cyclic DNA Adduct and Mutation in High-Fat Diet–induced Hepatocarcinogenesis by Theaphenon E
Authors: Coia Heidi , Ma Ning , Hou Yanqi , Dyba Marcin D. , Fu Ying , Cruz M. Idalia , Benitez Carlos , Graham Garrett T. , McCutcheon Justine N. , Zheng Yun-Ling , Sun Bing , Kallakury Bhaskar V. , Ma Junfeng , Fang Hong-Bin , Berry Deborah L. , Muralidaran Vinona , Chung Fung-Lung
Published: April 2023

Abstract
Obesity is associated with cancer risk and its link with liver cancer is particularly strong. Obesity causes non-alcoholic fatty liver disease (NAFLD) that could progress to hepatocellular carcinoma (HCC). Chronic inflammation likely plays a key role. We carried out a bioassay in the high-fat diet (HFD)-fed C57BL/6J mice to provide insight into the mechanisms of obesity-related HCC by studying γ-OHPdG, a mutagenic DNA adduct derived from lipid peroxidation. In an 80-week bioassay, mice received a low-fat diet (LFD), high-fat diet (HFD), and HFD with 2% Theaphenon E (TE) (HFD+TE). HFD mice developed a 42% incidence of HCC and LFD mice a 16%. Remarkably, TE, a standardized green tea extract formulation, completely blocked HCC in HFD mice with a 0% incidence. γ-OHPdG measured in the hepatic DNA of mice fed HFD and HFD+TE showed its levels increased during the early stages of NAFLD in HFD mice and the increases were significantly suppressed by TE, correlating with the tumor data. Whole-exome sequencing showed an increased mutation load in the liver tumors of HFD mice with G>A and G>T as the predominant mutations, consistent with the report that γ-OHPdG induces G>A and G>T. Furthermore, the mutation loads were significantly reduced in HFD+TE mice, particularly G>T, the most common mutation in human HCC. These results demonstrate in a relevant model of obesity-induced HCC that γ-OHPdG formation during fatty liver disease may be an initiating event for accumulated mutations that leads to HCC and this process can be effectively inhibited by TE. Cancer Prev Res; 11(10); 665–76. ©2018 AACR.
Data from Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma
Authors: Steinberger Kayla J. , Bailey Michael T. , Gross Amy C. , Sumner Laura A. , Voorhees Jeffrey L. , Crouser Nisha , Curry Jennifer M. , Wang Yijie , DeVries A. Courtney , Marsh Clay B. , Glaser Ronald , Yang Eric V. , Eubank Timothy D.
Published: April 2023

Abstract
Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-β-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2.
Data from Harnessing the Power of Cruciferous Vegetables: Developing a Biomarker for Brassica Vegetable Consumption Using Urinary 3,3′-Diindolylmethane
Authors: Fujioka Naomi , Ransom Benjamin W. , Carmella Steven G. , Upadhyaya Pramod , Lindgren Bruce R. , Roper-Batker Astia , Hatsukami Dorothy K. , Fritz Vincent A. , Rohwer Charles , Hecht Stephen S.
Published: April 2023

Abstract
Glucobrassicin in Brassica vegetables gives rise to indole-3-carbinol (I3C), a compound with potent anticancer effects in preclinical models. We previously showed that the urinary metabolite 3,3′-diindolylmethane (DIM) could discriminate between volunteers fed high and low doses of Brassica vegetables. However, the quantitative relationship between glucobrassicin exposure and urinary DIM level is unclear. We conducted a clinical trial to examine the hypotheses that a range of glucobrassicin exposure from Brassica vegetables is reflected in urinary DIM and that this effect plateaus. Forty-five subjects consumed vegetables, a mixture of brussels sprouts and/or cabbage, at one of seven discrete dose levels of glucobrassicin ranging from 25 to 500 μmol, once daily for 2 consecutive days. All urine was collected for 24 hours after each vegetable-eating session. Urinary DIM was measured using our published liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (LC/ESI-MS/MS-SRM) method. Urinary DIM excretion increased predictably with increasing glucobrassicin dose and plateaued between 200 and 300 μmol of glucobrassicin. The association between glucobrassicin dose and urinary DIM was strong and positive (R2 = 0.68). The majority of DIM was excreted in the first 12 hours after vegetable consumption. We conclude that urinary DIM is a reliable biomarker of glucobrassicin exposure and I3C uptake and that feeding glucobrassicin beyond 200 μmol did not consistently lead to more urinary DIM, suggesting a plateau in potential chemopreventive benefit. Cancer Prev Res; 9(10); 788–93. ©2016 AACR.
Data from A National Bowel Cancer Screening Programme using FIT: Achievements and Challenges
Authors: O'Donoghue Diarmuid , Sheahan Kieran , MacMathuna Padraic , Stephens Richard B. , Fenlon Helen , Morrin Martina , Mooney Jenny , Fahy Lorraine E. , Mooney Therese , Smith Alan
Published: April 2023

Abstract
Colorectal cancer accounts for 11% of all cancer-related deaths in Ireland. With the aim of diagnosing these cancers at an earlier stage, and detecting premalignant lesions, the National Screening Service (NSS) offered a fecal immunochemical test (FIT) to all individuals aged 60 to 69. All individuals in the age range were contacted by post and invited to participate in the programme. Those with a positive FIT result were offered a colonoscopy in an internationally accredited unit. From an eligible population of 488,628, 196,238 individuals participated giving an uptake of 40.2%. Commencing at a FIT threshold of 20 μg Hg/g feces, the positivity rate was 8.6%, which overwhelmed colonoscopy capacity and, thus, the threshold was increased to 45 μg, resulting in an overall 5% positivity rate. A total of 520 individuals had cancer detected (68.3% stage I or II), of which 104 were removed endoscopically (pT1s). Adenomas were present in 54.2% of all colonoscopies, 17.4% deemed high risk. Despite a lower uptake, males were twice as likely to have colorectal cancers as females and had a 59% increased rate of high-risk adenomas diagnosed. Challenges facing the programme include increasing participation, especially among males, and increasing colonoscopy capacity. The ability to alter the sensitivity of FIT to match colonoscopy capacity is a valuable option for such a programme as it ensures that the maximum public health benefit can be achieved within available resources.
Data from Sex-Specific Association between Family History of Diabetes and Risk of Colorectal Cancer: Two Prospective Cohort Studies
Authors: Ma Wenjie , Song Mingyang , Kværner Ane Sørlie , Prescott Jennifer , Chan Andrew , Giovannucci Edward , Zhang Xuehong
Published: April 2023

Abstract
Type 2 diabetes (T2D) is associated with increased risk of colorectal cancer. It remains unclear whether family history of diabetes influences colorectal cancer risk and relevant biomarkers. We followed 101,323 women from the Nurses’ Health Study (1982–2012) and 48,542 men from the Health Professionals Follow-up Study (1988–2012), free of cancer and inflammatory bowel disease at baseline. Participants reported whether any of their first-degree family members ever had diabetes in multiple questionnaires administered biennially. Plasma levels of colorectal cancer–related biomarkers were measured in subsets of participants from previous nested case–control studies. We documented 1,950 colorectal cancer cases in women and 1,173 colorectal cancer cases in men. After adjustment for potential confounders including obesity and diabetes, the hazard ratio (HR) for colorectal cancer among men who had family history of diabetes was 1.19 [95% confidence interval (CI), 1.04–1.36) as compared with those who did not. The corresponding HR was 1.06 among women (95% CI, 0.96–1.17). Interestingly, for individuals younger than 60 years, these associations appeared stronger among men (HR, 1.65; 95% CI, 1.15–2.38) and possibly among women (HR, 1.23; 95% CI, 0.99–1.54). Moreover, family history of diabetes was related to reduced levels of estradiol, sex hormone binding globulin (SHBG), and adiponectin in men, with a greater reduction of SHBG for those younger than 60 years (P for interaction = 0.03). In conclusion, family history of diabetes was associated with increased colorectal cancer risk in men, which may be partly mediated by altered sex hormones and adiponectin. The possible positive association in younger women needs further confirmation. Cancer Prev Res; 11(9); 535–44. ©2018 AACR.
Data from A Prospective Study of Nut Consumption and Risk of Primary Hepatocellular Carcinoma in the U.S. Women and Men
Authors: Sui Jing , Yang Wanshui , Ma Yanan , Li Tricia Y. , Simon Tracey G. , Meyerhardt Jeffrey A. , Liang Geyu , Giovannucci Edward L. , Chan Andrew T. , Zhang Xuehong
Published: April 2023

Abstract
Although increasing evidence suggests a potential beneficial effect of nut consumption on various diseases, no epidemiologic study has yet examined the association between nut consumption and risk of hepatocellular carcinoma (HCC). We prospectively examined this association in 88,783 women from the Nurses’ Health Study and 51,492 men from the Health Professionals Follow-up Study. Nut consumption was assessed every 4 years using validated food frequency questionnaires. Multivariable HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression models after adjusting for HCC risk factors. After an average of 27.9 years of follow-up, we identified a total of 162 incident HCC cases. Higher total nut consumption was not significantly associated with HCC risk (the highest vs. lowest tertile intake, HR, 0.84; 95% CI, 0.56–1.26). For the same comparison, higher tree nut consumption was associated with a lower HCC risk (HR, 0.64; 95% CI, 0.43–0.95). We found nonsignificant inverse associations with consumption of walnuts, peanuts, and peanut butter. Overall, nut consumption was not strongly associated with HCC risk. There was a suggestive inverse association with tree nut consumption. Future studies should carefully consider hepatitis B or C virus infections and examine these associations in other racial/ethnic groups.
Data from Effects of Black Raspberry Extract and Protocatechuic Acid on Carcinogen-DNA Adducts and Mutagenesis, and Oxidative Stress in Rat and Human Oral Cells
Authors: Guttenplan Joseph B. , Chen Kun-Ming , Sun Yuan-Wan , Kosinska Wieslawa , Zhou Ying , Kim Seungjin (Agatha) , Sung Youngjae , Gowda Krishne , Amin Shantu , Stoner Gary D. , El-Bayoumy Karam
Published: April 2023

Abstract
Effects of black raspberry (BRB) extract and protocatechuic acid (PCA) on DNA adduct formation and mutagenesis induced by metabolites of dibenzo[a,l]pyrene (DBP) were investigated in rat oral fibroblasts. The DBP metabolites, (±)-anti-11,12-dihydroxy-11,12,-dihydrodibenzo[a,l]pyrene (DBP-diol) and 11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) induced dose-dependent DNA adducts and mutations. DBPDE was considerably more potent, whereas the parent compound had no significant effect. Treatment with BRB extract (BRBE) and PCA resulted in reduced DBP-derived DNA adduct levels and reduced mutagenesis induced by DBP-diol, but only BRBE was similarly effective against (DBPDE). BRBE did not directly inactivate DBPDE, but rather induced a cellular response—enhanced DNA repair. When BRBE was added to cells 1 day after the DBP-diol, the BRBE greatly enhanced removal of DBP-derived DNA adducts. As oxidative stress can contribute to several stages of carcinogenesis, BRBE and PCA were investigated for their abilities to reduce oxidative stress in a human leukoplakia cell line by monitoring the redox indicator, 2′,7′-dichlorodihydrofluorescein diacetate (H2DCF) in cellular and acellular systems. BRBE effectively inhibited the oxidation, but PCA was only minimally effective against H2DCF. These results taken together provide evidence that BRBE and PCA can inhibit initiation of carcinogenesis by polycyclic aromatic hydrocarbons; and in addition, BRBE reduces oxidative stress. Cancer Prev Res; 9(8); 704–12. ©2016 AACR.
Data from Autofluorescence Imaging to Monitor the Progression of Oral Potentially Malignant Disorders
Authors: Cherry Katelin D. , Schwarz Richard A. , Yang Eric C. , Vohra Imran S. , Badaoui Hawraa , Williams Michelle D. , Vigneswaran Nadarajah , Gillenwater Ann M. , Richards-Kortum Rebecca
Published: April 2023

Abstract
Patients with oral potentially malignant disorders (OPMD) must undergo regular clinical surveillance to ensure that any progression to malignancy is detected promptly. Autofluorescence imaging (AFI) is an optical modality that can assist clinicians in detecting early cancers and high-grade dysplasia. Patients with OPMD undergoing surveillance for the development of oral cancer were examined using AFI at successive clinic visits. Autofluorescence images acquired at 133 clinical visits from sites in 15 patients who met inclusion criteria were analyzed quantitatively using an algorithm to calculate the red-to-green pixel intensity (RG ratio). A quantitative AFI threshold for high risk of progression was defined based on the RG ratio and was compared with expert clinical impression and with histopathology when available. Patients were divided into two groups based on their endpoint: surveillance (n = 6) or surgery (n = 9). In the surveillance group, 0 of 6 (0%) of patients were clinically identified as high risk for progression prior to the study endpoint, whereas 1 of 6 (17%) of patients were deemed at high risk for progression based on AFI during the same time period. In the surgery group, 9 of 9 (100%) of patients were clinically identified as high risk prior to the study endpoint, whereas 8 of 9 (89%) of patients were at high risk for progression based on AFI during the same time period. AFI results tracked over time were comparable with expert clinical impression in these patient groups. AFI has the potential to aid clinicians in noninvasively monitoring oral precancer and evaluating OPMDs that require increased surveillance.
Data from Breast Cancer Chemoprevention: Use and Views of Australian Women and Their Clinicians
Authors: Macdonald Courtney , Saunders Christobel M. , Keogh Louise A. , Hunter Morgan , Mazza Danielle , McLachlan Sue-Anne , Jones Sandra C. , Nesci Stephanie , Friedlander Michael L. , Hopper John L. , Emery Jon D. , Hickey Martha , Milne Roger L. , Phillips Kelly-Anne
Published: April 2023

Abstract
Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. Seven hundred twenty-five women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. Three hundred seventy-eight (52%) kConFab women, two (3%) breast surgeons, and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side effects (31%) and inadequate information (23%), which operate in the Theoretical Domains Framework domains of “beliefs about consequences” and “knowledge,” respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, “knowledge,” “beliefs about consequences,” and “goals” domains), staying healthy for family (13%, “social role” and “goals” domains), and abnormal breast biopsy (13%, “environmental context” domain). The strongest barrier for family physicians was insufficient knowledge (45%, “knowledge” domain) and for breast surgeons was medication side effects (40%, “beliefs about consequences” domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history, and better tools to select patients (“environmental context and resources” domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention, are key domains that could be targeted to potentially enhance uptake.
Prevention Relevance:
Despite its efficacy in reducing breast cancer incidence, chemoprevention is underutilised. This survey study of Australian women and their clinicians used behavioural change theory to identify modifiable barriers to chemoprevention uptake, and to suggest interventions such as policy change, educational resources and public campaigns, that may increase awareness and use.

See related Spotlight by Vogel, p. 1
Data from The Role of Lysosome-associated Membrane Protein 2 in Prostate Cancer Chemopreventive Mechanisms of Sulforaphane
Authors: Hahm Eun-Ryeong , Singh Krishna B. , Kim Su-Hyeong , Powolny Anna A. , Singh Shivendra V.
Published: April 2023

Abstract
Prostate cancer chemoprevention by sulforaphane, which is a metabolic by-product of glucoraphanin found in broccoli, in preclinical models is associated with induction of both apoptosis and autophagy. However, the molecular mechanism underlying sulforaphane-mediated autophagy, which is protective against apoptotic cell death by this phytochemical, is still poorly understood. This study demonstrates a role for lysosome-associated membrane protein 2 (LAMP2) in sulforaphane-mediated autophagy and apoptosis. Western blotting revealed dose-dependent induction of LAMP2 protein after treatment with sulforaphane as well as its naturally occurring analogs in PC-3 and 22Rv1 human prostate cancer cell lines that was confirmed by microscopy (sulforaphane). The mRNA level of LAMP2 was also increased upon treatment with sulforaphane in both cell lines. Sulforaphane-mediated increase in the level of autophagy marker microtubule-associated protein light-chain 3B was augmented by RNAi of LAMP2 in PC-3 and 22Rv1 cells. Apoptosis induction by sulforaphane treatment was also increased significantly by knockdown of the LAMP2 protein in PC-3 and 22Rv1 cells. Augmentation of sulforaphane-mediated apoptosis by RNAi of LAMP2 was accompanied by induction and activation of proapoptotic protein Bak. Oral administration of sulforaphane to TRAMP mice also resulted in induction of LAMP2 protein expression. Targeted microarray in sulforaphane-treated PC-3 cells revealed induction of many autophagy-related genes (e.g., HSP90AA1, NRF2, etc.) and their expression positively correlated with that of LAMP2 in prostate cancer The Cancer Genome Atlas. In conclusion, this study reveals that induction of LAMP2 by sulforaphane inhibits its ability to induce apoptotic cell death at least in human prostate cancer cells.
Data from Early Exposure to a High Fat/High Sugar Diet Increases the Mammary Stem Cell Compartment and Mammary Tumor Risk in Female Mice
Authors: Lambertz Isabel U. , Luo Linjie , Berton Thomas R. , Schwartz Scott L. , Hursting Stephen D. , Conti Claudio J. , Fuchs-Young Robin
Published: April 2023

Abstract
Obesity and alterations in metabolic programming from early diet exposures can affect the propensity to disease in later life. Through dietary manipulation, developing mouse pups were exposed to a hyperinsulinemic, hyperglycemic milieu during three developmental phases: gestation, lactation, and postweaning. Analyses showed that a postweaning high fat/high sugar (HF/HS) diet had the main negative effect on adult body weight, glucose tolerance, and insulin resistance. However, dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis revealed that animals born to a mother fed a HF/HS gestation diet, nursed by a mother on a mildly diet-restricted, low fat/low sugar diet (DR) and weaned onto a HF/HS diet (HF/DR/HF) had the highest mammary tumor incidence, while HF/HF/DR had the lowest tumor incidence. Cox proportional hazards analysis showed that a HF/HS postweaning diet doubled mammary cancer risk, and a HF/HS diet during gestation and postweaning increased risk 5.5 times. Exposure to a HF/HS diet during gestation, when combined with a postweaning DR diet, had a protective effect, reducing mammary tumor risk by 86% (HR = 0.142). Serum adipocytokine analysis revealed significant diet-dependent differences in leptin/adiponectin ratio and IGF-1. Flow cytometry analysis of cells isolated from mammary glands from a high tumor incidence group, DR/HF/HF, showed a significant increase in the size of the mammary stem cell compartment compared with a low tumor group, HF/HF/DR. These results indicate that dietary reprogramming induces an expansion of the mammary stem cell compartment during mammary development, increasing likely carcinogen targets and mammary cancer risk. Cancer Prev Res; 10(10); 553–62. ©2017 AACR.

See related editorial by Freedland, p. 551–2.
Data from A Multistage Murine Breast Cancer Model Reveals Long-Lived Premalignant Clones Refractory to Parity-Induced Protection
Authors: Li Shuo , Gestl Shelley A. , Gunther Edward J.
Published: April 2023

Abstract
Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a subclinical state prior to completing malignant transformation, yet widely used breast cancer models lack an experimental framework for targeting premalignant disease. Inspired by classic multistage skin carcinogenesis protocols, we combined chemical carcinogenesis with transgenic mouse modeling to resolve mouse mammary carcinogenesis into discrete initiation and progression stages. At the initiation stage, exposure to the carcinogen 7,12-dimethylbenzanthracene (DMBA) generated “initiated mammary epithelial cells” (iMEC) by introducing a stereotyped HrasQ61L driver mutation. Whether DMBA exposure occurred during puberty or adulthood, mice efficiently acquired iMEC clones that eluded detection by conventional histology, yet were long lived, persisting in a clinically silent state for months in the absence of a cooperating event. At the progression stage, inducible activation of oncogenic Wnt signaling drove rapid and synchronous transformation of latent iMECs into overt mammary carcinomas, while Wnt activation in neighboring normal mammary epithelium yielded only benign hyperplasia over this same time period. Although early parity (completion of a full-term pregnancy) reduces breast cancer risk in some contexts, standard parity-induced protection schemes failed to eliminate iMECs in our multistage model, suggesting Wnt-responsive iMECs are maintained by hormone-independent mechanisms. Variations on our multistage modeling strategy may help to identify and validate cellular and molecular targets for breast cancer chemoprevention.
Data from Clinical Trial of 2-Phenethyl Isothiocyanate as an Inhibitor of Metabolic Activation of a Tobacco-Specific Lung Carcinogen in Cigarette Smokers
Authors: Yuan Jian-Min , Stepanov Irina , Murphy Sharon E. , Wang Renwei , Allen Sharon , Jensen Joni , Strayer Lori , Adams-Haduch Jennifer , Upadhyaya Pramod , Le Chap , Kurzer Mindy S. , Nelson Heather H. , Yu Mimi C. , Hatsukami Dorothy , Hecht Stephen S.
Published: April 2023

Abstract
2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in watercress and other cruciferous vegetables, is an inhibitor of the metabolic activation and lung carcinogenicity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in F344 rats and A/J mice. We carried out a clinical trial to determine whether PEITC also inhibits the metabolic activation of NNK in smokers. Cigarette smokers were recruited and asked to smoke cigarettes containing deuterium-labeled [pyridine-D4]NNK for an acclimation period of at least 1 week. Then subjects were randomly assigned to one of two arms: PEITC followed by placebo, or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. The NNK metabolic activation ratio [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL was measured in urine samples to test the hypothesis that PEITC treatment modified NNK metabolism. Eighty-two smokers completed the study and were included in the analysis. Overall, the NNK metabolic activation ratio was reduced by 7.7% with PEITC treatment (P = 0.023). The results of this trial, while modest in effect size, provide a basis for further investigation of PEITC as an inhibitor of lung carcinogenesis by NNK in smokers. Cancer Prev Res; 9(5); 396–405. ©2016 AACR.
Data from Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo
Authors: Kumar Dileep , Rahman Hafeez , Tyagi Ethika , Liu Tong , Li Chelsea , Lu Ran , Lum David , Holmen Sheri L. , Maschek J. Alan , Cox James E. , VanBrocklin Matthew W. , Grossman Douglas
Published: April 2023

Abstract
There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5′-adenosine monophosphate–activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo. This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629–42. ©2018 AACR.
Data from Physical Activity and Long-term Quality of Life among Colorectal Cancer Survivors—A Population-based Prospective Study
Authors: Eyl Ruth Elisa , Koch-Gallenkamp Lena , Jansen Lina , Walter Viola , Carr Prudence R. , Hoffmeister Michael , Chang-Claude Jenny , Brenner Hermann , Arndt Volker
Published: April 2023

Abstract
Evidence suggests that physical activity (PA) is positively associated with (health-related) quality of life (QOL) in colorectal cancer survivors. However, little is known regarding long-term effects of PA on QOL and if prediagnosis PA is associated with QOL in the years after diagnosis. Our study aimed to investigate the association of prediagnosis and postdiagnosis PA with long-term QOL in colorectal cancer survivors.

This study is based on a population-based cohort from Germany of 1,781 newly diagnosed colorectal cancer survivors over a 5-year period. PA was assessed at diagnosis and at 5-year follow-up (5YFU). Quality of life was assessed by the European Organisation for Research and Treatment of Cancer C Quality of Life Questionnaire QLQ-C30 at 5YFU. Multivariable linear regression was used to explore associations between prediagnosis and postdiagnosis PA and QOL at 5YFU.

No evidence of a positive association between higher levels of prediagnosis PA and better long-term QOL was found. Higher levels of prediagnosis work-related PA and vigorous PA were even associated with decreased QOL in domains such as cognitive [Beta(β) = −2.52, 95% confidence interval (CI) = −3.77, −1.27; β = −1.92, CI = −3.17, −0.67) and emotional functioning (β = −2.52, CI = −3.84, −1.19; β = −2.12, CI = −3.44, −0.80). In cross-sectional analyses, higher postdiagnosis PA was strongly associated with higher QOL. Survivors physically active at both prediagnosis and postdiagnosis as well as survivors who increased their PA between prediagnosis and postdiagnosis reported significantly higher long-term QOL compared with survivors who remained inactive at prediagnosis and postdiagnosis. In this study, higher prediagnosis PA does not appear to be associated with higher QOL among long-term colorectal cancer survivors but our results support the importance of ongoing PA throughout survivorship.
Data from Interception Targets of Angelica Gigas Nakai Root Extract versus Pyranocoumarins in Prostate Early Lesions and Neuroendocrine Carcinomas in TRAMP Mice
Authors: Tang Su-Ni , Jiang Peixin , Kim Sangyub , Zhang Jinhui , Jiang Cheng , Lü Junxuan
Published: April 2023

Abstract
We reported efficacy of Angelica gigas Nakai (AGN) root ethanol extract and equimolar decursin (D)/decursinol angelate (DA) through daily gavage starting at 8 weeks of age (WOA) to male transgenic adenocarcinoma of mouse prostate (TRAMP) mice such that these modalities suppressed precancerous epithelial lesions in their dorsolateral prostate (DLP) to similar extent, but AGN extract was better than the D/DA mixture at promoting the survival of mice bearing prostate neuroendocrine carcinomas to 28 WOA. Here, we compared by microarray hybridization the mRNA levels in pooled DLP tissues and individual neuroendocrine carcinomas to characterize potential molecular targets of AGN extract and D/DA. Clustering and principal component analyses supported distinct gene expression profiles of TRAMP DLP versus neuroendocrine carcinomas. Pathway Enrichment, Gene Ontology, and Ingenuity Pathway Analyses of differential genes indicated that AGN and D/DA affected chiefly processes of lipid and mitochondrial energy metabolism and oxidation-reduction in TRAMP DLP, while AGN affected neuronal signaling, immune systems and cell cycling in neuroendocrine carcinomas. Protein–Protein Interaction Network analysis predicted and reverse transcription-PCR verified multiple hub genes common in the DLP of AGN- and D/DA-treated TRAMP mice at 28 WOA and select hub genes attributable to the non-D/DA AGN components. The vast majority of hub genes in the AGN-treated neuroendocrine carcinomas differed from those in TRAMP DLP. In summary, the transcriptomic approach illuminated vastly different signaling pathways and networks, cellular processes, and hub genes of two TRAMP prostate malignancy lineages and their associations with the interception efficacy of AGN and D/DA.
Prevention Relevance:
This study explores potential molecular targets associated with in vivo activity of AGN root alcoholic extract and its major pyranocoumarins to intercept precancerous epithelial lesions and early malignancies of the prostate. Without an ethically-acceptable, clearly defined cancer initiation risk reduction strategy available for the prostate, using natural products like AGN to delay formation of malignant tumors could be a plausible approach for prostate cancer prevention.
Data from Proton Pump Inhibitor Omeprazole Suppresses Carcinogen-induced Colonic Adenoma Progression to Adenocarcinoma in F344 Rat
Authors: Madka Venkateshwar , Kumar Gaurav , Pathuri Gopal , Panneerselvam Janani , Zhang Yuting , Ganta Vishal , Lightfoot Stanley , Lubet Ronald , Suen Chen S. , Steele Vernon E. , Janakiram Naveena B. , Mohammed Altaf , Rao Chinthalapally V.
Published: April 2023

Abstract
Colorectal cancer causes over 53,000 deaths annually in the United States. Its rising incidences worldwide and particularly in young adults is a major concern. Here, we evaluated the efficacy of omeprazole that is clinically approved for treating acid reflux, to enable its repurposing for colorectal cancer prevention. In the azoxymethane-induced rat colorectal cancer model, dietary omeprazole (250 and 500 ppm) was administered at early adenoma stage (8 weeks after azoxymethane) to assess the progression of early lesions to adenocarcinoma. Administration of omeprazole at 250 or 500 ppm doses led to suppression of total colon adenocarcinoma incidence by 15.7% and 32% (P < 0.01), respectively. Importantly, invasive carcinoma incidence was reduced by 59% (P < 0.0005) and 90% (P < 0.0001) in omeprazole-administered rats in a dose-dependent manner. There was also a strong and dose-dependent inhibition in the adenocarcinoma multiplicity in rats exposed to omeprazole. Administration of 250 and 500 ppm omeprazole inhibited total colon adenocarcinoma multiplicity by approximately 49% and approximately 65% (P < 0.0001), respectively. While noninvasive adenocarcinomas multiplicity was suppressed by approximately 34% to approximately 48% (P < 0.02), the invasive carcinomas multiplicity was reduced by approximately 74% to approximately 94% (P < 0.0001) in omeprazole-exposed rats in comparison with the untreated rats. Biomarker analysis results showed a decrease in cell proliferation and anti-apoptotic/pro-survival proteins with an increase in apoptosis. Transcriptome analysis of treated tumors revealed a significant increase in adenocarcinoma inhibitory genes (Olmf4; Spink4) expression and downregulation of progression promoting genes (SerpinA1, MMP21, IL6). In summary, omeprazole showed significant protection against the progression of adenoma to adenocarcinoma.
Prevention Relevance:
Preventing colon cancer is urgently needed because of its high incidence and mortality rates worldwide. Toward this end, preventive efficacy of omeprazole, a common medication, was evaluated in animal model of colorectal cancer and was found to suppress colonic adenoma progression to carcinoma. These findings warrant its further evaluation in humans.
Data from Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development
Authors: Chu Nina J. , Anders Robert A. , Fertig Elana J. , Cao Minwei , Hopkins Alexander C. , Keenan Bridget P. , Popovic Aleksandra , Armstrong Todd D. , Jaffee Elizabeth M. , Zimmerman Jacquelyn W.
Published: April 2023

Abstract
Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. In vivo miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies.
Data from Risk Factors for Recurrence in Patients with Atypical Endometrial Hyperplasia and Endometrioid Adenocarcinoma after Fertility-Sparing Treatments
Authors: Yin Jie , Ma Shuai , Shan Ying , Wang Yongxue , Li Yan , Jin Ying , Pan Lingya
Published: April 2023

Abstract
The aim of this work was to evaluate the risk factors for recurrence in young patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma after fertility-sparing treatments (FST). A retrospective case–control study was designed. Patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma who received FSTs from January 2010 to December 2017 were reviewed. All patients who met the inclusion criteria were divided into a recurrence group and a control group. Risk factors for recurrence- and disease-free survival were evaluated by logistic regression analysis and Cox regression analysis. A total of 127 patients were included, 53 patients in the recurrence group and 74 patients in the control group. No deaths occurred during the follow-up time. The rate of successful pregnancy was 62.5% in the control group and 20.5% in the recurrence group after complete remission (CR) of the primary disease. In a multivariate regression model, after adjusting for other factors, menstruation cycle, progestin type, and regular maintenance treatments after CR were the main risk factors for disease recurrence. Gonadotropin-releasing hormone agonist was mainly used to treat obese patients and was associated with longer progression-free survival (PFS) time compared with that in patients who received high-dose oral progestin such as megestrol acetate [risk ratio (RR), 2.158; 95% confidence interval (CI), 0.948–4.913]. Regular oral progestin also significantly prolonged the PFS time (RR, 4.726; 95% CI, 2.672–8.359). The progestin type used in treatment and regular maintenance treatment of young patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma after CR might be correlated with disease recurrence.