bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Large Prospective Study of SEP15 Genetic Variation, Interaction with Plasma Selenium Levels, and Prostate Cancer Risk and Survival
Authors: Penney Kathryn L. , Schumacher Fredrick R. , Li Haojie , Kraft Peter , Morris J. Steven , Kurth Tobias , Mucci Lorelei A. , Hunter David J. , Kantoff Philip W. , Stampfer Meir J. , Ma Jing
Published: March 2024

Abstract
The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R2 > 0.8) within SEP15, as well as rs5859 in the 3′ untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (Pinteraction = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype. Cancer Prev Res; 3(5); 604–10. ©2010 AACR.
Data from Celecoxib Inhibits Interleukin-6/Interleukin-6 Receptor–Induced JAK2/STAT3 Phosphorylation in Human Hepatocellular Carcinoma Cells
Authors: Liu Yan , Liu Aiguo , Li Huameng , Li Chenglong , Lin Jiayuh
Published: March 2024

Abstract
Growing evidence shows an association between chronic liver inflammation and hepatocellular carcinoma (HCC) development. STAT3, which is associated with inflammation and cellular transformation, is constitutively activated in human HCC tissues but not in normal human liver tissues. Although interleukin-6 (IL-6) is elevated in the serum of patients with HCC, it is not fully understood whether STAT3 constitutive activation is positively correlated with autocrine IL-6 secreted by HCC cells. Here, we reported that in HCC cells, the elevated levels of both IL-6 and IL-6 receptor (IL-6R, gp80), not IL-6 alone, correlated with STAT3 activation. We also explored whether the anticancer effects of celecoxib, an anti-inflammatory drug, may be due to the inhibition of the IL-6/STAT3 pathway in HCC cells. Our results showed that celecoxib decreased STAT3 phosphorylation by reducing Janus-activated kinase (JAK2) phosphorylation and caused apoptosis in HCC cells. Celecoxib could also block exogenous IL-6–induced STAT3 phosphorylation and nuclear translocation. Moreover, we observed more significant inhibition of cell viability when celecoxib was combined with doxorubicin or sorafenib. We conclude that the elevated levels of IL-6/IL-6R may be correlated with STAT3 activation in HCC cells. Celecoxib may be a candidate for HCC therapy through blocking IL-6/STAT3 pathway and can be combined with other anticancer drugs to reduce drug resistance caused by IL-6/STAT3 signals. Cancer Prev Res; 4(8); 1296–305. ©2011 AACR.
Data from Endothelin Receptor Type B Gene Promoter Hypermethylation in Salivary Rinses Is Independently Associated with Risk of Oral Cavity Cancer and Premalignancy
Authors: Pattani Kavita Malhotra , Zhang Zhe , Demokan Semra , Glazer Chad , Loyo Myriam , Goodman Steven , Sidransky David , Bermudez Francisco , Jean-Charles Germain , McCaffrey Thomas , Padhya Tapan , Phelan Joan , Spivakovsky Silvia , Bowne Helen Yoo , Goldberg Judith D. , Rolnitzky Linda , Robbins Miriam , Kerr A. Ross , Sirois David , Califano Joseph A.
Published: March 2024

Abstract
Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination. Cancer Prev Res; 3(9); 1093–103. ©2010 AACR.
Data from Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis in Male Mice through Activation of the Wnt/β-Catenin Signaling Pathway
Authors: Mercer Kelly E. , Hennings Leah , Sharma Neha , Lai Keith , Cleves Mario A. , Wynne Rebecca A. , Badger Thomas M. , Ronis Martin J.J.
Published: March 2024

Abstract
Although alcohol effects within the liver have been extensively studied, the complex mechanisms by which alcohol causes liver cancer are not well understood. It has been suggested that ethanol (EtOH) metabolism promotes tumor growth by increasing hepatocyte proliferation. In this study, we developed a mouse model of tumor promotion by chronic EtOH consumption in which EtOH feeding began 46 days after injection of the chemical carcinogen diethylnitrosamine (DEN) and continued for 16 weeks. With a final EtOH concentration of 28% of total calories, we observed a significant increase in the total number of preneoplastic foci and liver tumors per mouse in the EtOH+DEN group compared with corresponding pair-fed (PF)+DEN and chow+DEN control groups. We also observed a 4-fold increase in hepatocyte proliferation (P < 0.05) and increased cytoplasmic staining of active-β-catenin in nontumor liver sections from EtOH+DEN mice compared with PF+DEN controls. In a rat model of alcohol-induced liver disease, we found increased hepatocyte proliferation (P < 0.05); depletion of retinol and retinoic acid stores (P < 0.05); increased expression of cytosolic and nuclear expression of β-catenin (P < 0.05) and phosphorylated-glycogen synthase kinase 3β (p-GSK3β), P < 0.05; significant upregulation in Wnt7a mRNA expression; and increased expression of several β-catenin targets, including, glutamine synthetase (GS), cyclin D1, Wnt1 inducible signaling pathways protein (WISP1), and matrix metalloproteinase-7(MMP7), P < 0.05. These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathways to increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver. Cancer Prev Res; 7(7); 675–85. ©2014 AACR.
Data from A DRD1 Polymorphism Predisposes to Lung Cancer among Those Exposed to Secondhand Smoke during Childhood
Authors: Robles Ana I. , Yang Ping , Jen Jin , McClary Andrew C. , Calhoun Kara , Bowman Elise D. , Vähäkangas Kirsi , Greathouse K. Leigh , Wang Yi , Olivo-Marston Susan , Wenzlaff Angela S. , Deng Bo , Schwartz Ann G. , Ryan Bríd M.
Published: March 2024

Abstract
Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.
Data from Inhibition of Endometrial Cancer by n-3 Polyunsaturated Fatty Acids in Preclinical Models
Authors: Zheng Hang , Tang Hongjun , Liu Miao , He Minhong , Lai Pinglin , Dong Heling , Lin Jun , Jia Chunhong , Zhong Mei , Dai Yifan , Bai Xiaochun , Wang Liping
Published: March 2024

Abstract
Although preclinical and epidemiologic studies have shown the importance of n-3 polyunsaturated fatty acids (PUFA) in the prevention of hormone-responsive cancers such as breast cancer, evidence of the association between n-3 PUFAs and endometrial cancer risk is limited and no previous study has examined the effect of n-3 PUFAs on endometrial cancer in cellular and animal models. In this study, we demonstrated that docosahexenoic acid (DHA) dose- and time-dependently inhibited endometrial cancer cell proliferation, colony formation, and migration and promoted apoptosis. Dietary n-3 PUFAs efficiently prevented endometrial cancer cell growth in xenograft models. Moreover, ectopic expression of fat-1, a desaturase, catalyzed the conversion of n-6 to n-3 PUFAs and produced n-3 PUFAs endogenously, also suppressed endometrial tumor cell growth and migration, and potentiated apoptosis in endometrial cancer cell lines. Interestingly, implanted endometrial cancer cells were unable to grow in fat-1 transgenic SCID mice. Further study revealed that mTOR signaling, which plays an essential role in cell proliferation and endometrial tumorigenesis, is a target of n-3 PUFAs. Exogenous or endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 in vitro and in vivo. Moreover, both dietary n-3 PUFAs and transgenic expression of fat-1 in mice effectively repressed mTORC1/2 signaling and endometrial growth elicited by unopposed estrogen. Taken together, our findings provide comprehensive preclinical evidences that n-3 PUFAs efficiently prevent endometrial cancer and establish mTORC1/2 as a target of n-3 PUFAs. Cancer Prev Res; 7(8); 824–34. ©2014 AACR.
Data from Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β
Authors: Chen Xiangmei , Zhang Ling , Zheng Sujun , Zhang Ting , Li Meng , Zhang Xiaolei , Zeng Zhenzhen , McCrae Malcolm A. , Zhao Jingmin , Zhuang Hui , Lu Fengmin
Published: March 2024

Abstract
The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40–60 minutes to 80–110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3β, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3β along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3β. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression. Cancer Prev Res; 8(5); 455–63. ©2015 AACR.
Data from Breast Cancer Risk in Young Women in the National Breast Screening Programme: Implications for Applying NICE Guidelines for Additional Screening and Chemoprevention
Authors: Evans D. Gareth , Brentnall Adam R. , Harvie Michelle , Dawe Sarah , Sergeant Jamie C. , Stavrinos Paula , Astley Susan , Wilson Mary , Ainsworth John , Cuzick Jack , Buchan Iain , Donnelly Louise S. , Howell Anthony
Published: March 2024

Abstract
In the United Kingdom, women at moderate and high risk of breast cancer between the ages of 40 and 49 years are eligible for annual mammographic screening and preventive therapy with tamoxifen. Here, we estimate the numbers of women in a population eligible for this service and the proportion of breast cancers detected in this group compared with the whole population. Women <50 attending for mammographic screening in the National Health Service Breast Screening Programme (NHSBSP) completed a risk questionnaire. The proportion at moderate and high risk according to National Institute of Health Care Excellence (NICE) guidelines was estimated. An estimate was also made using a different model of risk estimation (Tyrer–Cuzick). The numbers of cancers detected in the moderate/high risk groups were compared with numbers detected in the whole population. Completed questionnaires were available for 4,360 women between ages 46 and 49 years. Thirty women [0.7%; 95% confidence interval (CI), 0.5–1.0%] were at high risk and 130 (3.0%, 2.5–3.5%) were at moderate risk according to NICE guidelines. Thirty-seven cancers were detected by mammography in the whole group. Five of these were found in the moderate-/high-risk group giving a 3.2-fold increase in detection compared with the standard risk group. More women were assigned to the moderate- or high-risk group using the Tyrer–Cuzick model (N = 384), but the numbers of cancers in this group were not appreciably increased (N = 8). Systematic assessment of family history in primary care or through population-based screening will identify appreciable numbers of women in their forties, eligible for additional surveillance and chemoprevention Cancer Prev Res; 7(10); 993–1001. ©2014 AACR.
Data from An Evaluation of Novel, Lower-Cost Molecular Screening Tests for Human Papillomavirus in Rural China
Authors: Zhao Fang-Hui , Jeronimo Jose , Qiao You-Lin , Schweizer Johannes , Chen Wen , Valdez Melissa , Lu Peter , Zhang Xun , Kang Le-Ni , Bansil Pooja , Paul Proma , Mahoney Charles , Berard-Bergery Marthe , Bai Ping , Peck Roger , Li Jing , Chen Feng , Stoler Mark H. , Castle Philip E.
Published: March 2024

Abstract
New, lower-cost tests that target high-risk human papillomavirus (HR-HPV) have been developed for cervical cancer screening in lower-resource settings but large, population-based screening studies are lacking. Women ages 25 to 65 years and living in rural China (n = 7,543) self-collected a cervicovaginal specimen, had 2 cervical specimens collected by a clinician, and underwent visual inspection after acetic acid (VIA). The self- and one clinician-collected specimens underwent HR-HPV DNA testing by careHPV (QIAGEN) and Hybrid Capture 2 (HC2; QIAGEN) and the other clinician-collected specimen was tested for HPV16, 18, and 45 E6 using OncoE6 (Arbor Vita Corporation). Women who screened positive for any test and a random sample of those negative on all tests underwent colposcopic evaluation. The percent test positive was 1.8% for HPV E6 oncoprotein, between 14% and 18% for HR-HPV DNA testing, and 7.3% for VIA. The sensitivity for cervical intraepithelial neoplasia grade 3 or more severe (CIN3+; n = 99) was 53.5% for OncoE6, 97.0% for both careHPV and HC2 testing of the clinician-collected specimen, 83.8% for careHPV testing and 90.9% for HC2 testing of the self-collected specimen, and 50.5% for VIA. OncoE6 had the greatest positive predictive value (PPV), at 40.8% for CIN3+, compared with the other tests, which had a PPV of less than 10%. OncoE6 tested 70.3% positive for HPV16, 18, or 45-positive CIN3+ and tested negative for all HPV16-, 18-, or 45-negative CIN3+ (P < 0.0001). HPV E6 oncoprotein detection is useful for identifying women who have cervical precancer and cancer. Cancer Prev Res; 6(9); 938–48. ©2013 AACR.
Data from Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens
Authors: Cramer Daniel W. , Bast Robert C. , Berg Christine D. , Diamandis Eleftherios P. , Godwin Andrew K. , Hartge Patricia , Lokshin Anna E. , Lu Karen H. , McIntosh Martin W. , Mor Gil , Patriotis Christos , Pinsky Paul F. , Thornquist Mark D. , Scholler Nathalie , Skates Steven J. , Sluss Patrick M. , Srivastava Sudhir , Ward David C. , Zhang Zhen , Zhu Claire S. , Urban Nicole
Published: March 2024

Abstract
Establishing a cancer screening biomarker's intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network or Ovarian Cancer Specialized Program of Research Excellence sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within 6 months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study. Cancer Prev Res; 4(3); 365–74. ©2011 AACR.
Data from Postmenopausal Serum Sex Steroids and Risk of Hormone Receptor–Positive and -Negative Breast Cancer: a Nested Case–Control Study
Authors: James Rebecca E. , Lukanova Annekatrin , Dossus Laure , Becker Susen , Rinaldi Sabina , Tjønneland Anne , Olsen Anja , Overvad Kim , Mesrine Sylvie , Engel Pierre , Clavel-Chapelon Françoise , Chang-Claude Jenny , Vrieling Alina , Boeing Heiner , Schütze Madlen , Trichopoulou Antonia , Lagiou Pagona , Trichopoulos Dimitrios , Palli Domenico , Krogh Vittorio , Panico Salvatore , Tumino Rosario , Sacerdote Carlotta , Rodríguez Laudina , Buckland Genevieve , Sánchez Maria-José , Amiano Pilar , Ardanaz Eva , Bueno-de-Mesquita Bas , Ros Martine M. , van Gils Carla H. , Peeters Petra H. , Khaw Kay-Tee , Wareham Nick , Key Timothy J. , Allen Naomi E. , Romieu Isabelle , Siddiq Afshan , Cox David , Riboli Elio , Kaaks Rudolf
Published: March 2024

Abstract
Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case–control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone–binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62–5.23), Ptrend = 0.002; testosterone OR = 2.27 (95% CI: 1.35–3.81), Ptrend = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00–4.46), Ptrend = 0.05; testosterone OR = 2.06 (95% CI: 0.95–4.46), Ptrend = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor–negative as well as receptor–positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors. Cancer Prev Res; 4(10); 1626–35. ©2011 AACR.
Data from Dietary Vitamin D and Vitamin D Receptor Level Modulate Epithelial Cell Proliferation and Apoptosis in the Prostate
Authors: Kovalenko Pavlo L. , Zhang Zhentao , Yu Jun-Ge , Li Yan , Clinton Steven K. , Fleet James C.
Published: March 2024

Abstract
Low vitamin D (VD) status may increase prostate cancer risk but experimental evidence for this relationship is modest. We tested whether low VD status or VD receptor (VDR) deletion influences prostate epithelial cell (PEC) biology using intact mice, castrated mice, or castrated mice treated with testosterone propionate (TP, 2.5 mg/kg BW). PEC proliferation (Ki-67 staining) and apoptosis (TUNEL method) were determined in the anterior prostate (AP). In study 1, wild-type (WT) and TgAPT121 mice (a model of prostate intraepithelial neoplasia) were fed diets with 25, 200 (reference diet), or 10,000 IU VD/kg diet (as vitamin D3) prior to castration/repletion. Serum 25 hydroxyvitamin D levels were 26, 78, and 237 nmol/L in the three diet groups, respectively. Castration reduced proliferation and increased apoptosis in the AP while TP reversed these effects. Low VD diet increased proliferation in WT (+82%) and TgAPT121 (+24%) mice while it suppressed apoptosis in WT (−29%) and TgAPT121 (−37%) mice. This diet also increased the severity of prostate intraepithelial neoplastic lesions in the AP of intact TgAPT121 mice. In study 2, mice with PEC-specific VDR deletion (PEC VDR KO) were examined after castration/repletion. TUNEL staining was 60% lower in castrated PEC VDR KO mice compared with castrated WT mice. In castrated mice given TP, Ki-67 staining was 2-fold higher in PEC VDR KO compared with WT mice. Our data show that low diet VDR or VDR deletion provide a prostate environment that is permissive to early procarcinogenic events that enhance prostate cancer risk. Cancer Prev Res; 4(10); 1617–25. ©2011 AACR.
Data from Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis
Authors: Hikita Hayato , Kodama Takahiro , Tanaka Satoshi , Saito Yoshinobu , Nozaki Yasutoshi , Nakabori Tasuku , Shimizu Satoshi , Hayashi Yoshito , Li Wei , Shigekawa Minoru , Sakamori Ryotaro , Miyagi Takuya , Hiramatsu Naoki , Tatsumi Tomohide , Takehara Tetsuo
Published: March 2024

Abstract
Chronic hepatitis, including viral hepatitis and steatihepatitis, is a well-known high-risk condition for hepatocellular carcinoma. We previously reported that continuous hepatocyte apoptosis drives liver tumors in hepatocyte-specific Bcl-xL or Mcl-1 knockout mice. In this study, we further examine the underlying cellular mechanisms of generating tumors in apoptosis-prone liver. In cultured hepatocytes, the administration of ABT-737, a Bcl-xL/-2/-w inhibitor, led to production of reactive oxygen species (ROS) as well as activation of caspases. Mitochondria isolated from murine liver, upon administration of truncated-Bid, a proapoptotic Bcl-2 family protein, released cytochrome c and produced ROS, which was dependent on mitochondrial respiration. Hepatic apoptosis, regeneration, accumulation of oxidative damages, and tumorigenesis observed in hepatocyte-specific Mcl-1 knockout mice were substantially attenuated by further deficiency of Bax or Bid, suggesting that a balance of mitochondrial Bcl-2 family proteins governs generation of oxidative stress and other pathologies. Whole-exome sequencing clarified that C>A/G>T transversion, which is often caused by oxidative DNA damage in proliferating cells, was a frequently observed mutation pattern in liver tumors of Mcl-1 knockout mice. The administration of antioxidant L-N-acetylcysteine did not affect apoptosis, compensatory regeneration, or fibrotic responses but significantly reduced oxidative DNA damage and incidence and multiplicity of live tumors in Mcl-1 knockout mice. In conclusion, activation of the mitochondrial apoptotic pathway in hepatocytes accumulates intracellular oxidative damages, leading to liver tumorigenesis, independently of liver regeneration or fibrosis. This study supports a concept that antioxidant therapy may be useful for suppressing liver carcinogenesis in patients with chronic liver disease. Cancer Prev Res; 8(8); 693–701. ©2015 AACR.
Data from Notch1 Mutations Are Drivers of Oral Tumorigenesis
Authors: Izumchenko Evgeny , Sun Kai , Jones Sian , Brait Mariana , Agrawal Nishant , Koch Wayne , McCord Christine L. , Riley David R. , Angiuoli Samuel V. , Velculescu Victor E. , Jiang Wei-Wen , Sidransky David
Published: March 2024

Abstract
Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput PCR-based enrichment technology and next-generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty-nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies, and 50 were chemoradiation-naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of premalignant lesions. Importantly, almost 60% of patients with leukoplakia with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese patients with OSCC with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that premalignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations. Cancer Prev Res; 8(4); 277–86. ©2014 AACR.

See related perspectives, p. 259 and p. 262
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: March 2024

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 Testing Novel Pyrimidinyl Rexinoids: A New Paradigm for Evaluating Rexinoids for Cancer Prevention
Authors: Zhang Di , Leal Ana S. , Carapellucci Sarah , Shahani Pritika H. , Bhogal Jaskaran S. , Ibrahim Samir , Raban San , Jurutka Peter W. , Marshall Pamela A. , Sporn Michael B. , Wagner Carl E. , Liby Karen T.
Published: March 2024

Abstract
Rexinoids, selective ligands for retinoid X receptors (RXR), have shown promise in preventing many types of cancer. However, the limited efficacy and undesirable lipidemic side-effects of the only clinically approved rexinoid, bexarotene, drive the search for new and better rexinoids. Here we report the evaluation of novel pyrimidinyl (Py) analogues of two known chemopreventive rexinoids, bexarotene (Bex) and LG100268 (LG268) in a new paradigm. We show that these novel derivatives were more effective agents than bexarotene for preventing lung carcinogenesis induced by a carcinogen. In addition, these new analogues have an improved safety profile. PyBex caused less elevation of plasma triglyceride levels than bexarotene, while PyLG268 reduced plasma cholesterol levels and hepatomegaly compared with LG100268. Notably, this new paradigm mechanistically emphasizes the immunomodulatory and anti-inflammatory activities of rexinoids. We reveal new immunomodulatory actions of the above rexinoids, especially their ability to diminish the percentage of macrophages and myeloid-derived suppressor cells in the lung and to redirect activation of M2 macrophages. The rexinoids also potently inhibit critical inflammatory mediators including IL6, IL1β, CCL9, and nitric oxide synthase (iNOS) induced by lipopolysaccharide. Moreover, in vitro iNOS and SREBP (sterol regulatory element-binding protein) induction assays correlate with in vivo efficacy and toxicity, respectively. Our results not only report novel pyrimidine derivatives of existing rexinoids, but also describe a series of biological screening assays that will guide the synthesis of additional rexinoids. Further progress in rexinoid synthesis, potency, and safety should eventually lead to a clinically acceptable and useful new drug for patients with cancer.
Data from Risk Prediction of Cervical Cancer and Precancers by Type-Specific Human Papillomavirus: Evidence from a Population-Based Cohort Study in China
Authors: Dong Li , Hu Shang-Ying , Zhang Qian , Feng Rui-Mei , Zhang Li , Zhao Xue-Lian , Zhang Xun , Qiao You-Lin , Zhao Fang-Hui
Published: March 2024

Abstract
Risk stratification of human papillomavirus (HPV)-positive women is needed to avoid excessive colposcopy and overtreatment in cervical cancer screening. We aimed to evaluate the predictive value of type-specific HPV in detecting cervical cancer and precancers in a Chinese population–based cohort and provide evidence of HPV genotyping to triage HPV-positive women. We typed all Hybrid Capture 2–positive cytologic samples of 1,742 women in Shanxi Province Cervical Cancer Screening Study cohort. Cumulative risks of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPV-positive women and cumulative detection rates of CIN2+ among general women by type-specific HPV were estimated during the course of 10-year follow-up. HPV 16 and HPV 52 were most prevalent types among the screening population. Ten-year cumulative risk of CIN2+ was 47.5% [95% confidence interval (CI), 31.6–62.3] for HPV 16–positive women and 46.3% (95% CI, 15.3–75.4) for HPV 31–positive women. Ten-year cumulative risks of CIN2+ among HPV 58, 39, 33, 18, and 52 positive women ranged from 34.3% to 12.0% in a decreasing order. CIN2+ risks were found to be positively associated with infection times of the same genotypes of HPV 16, 31, 33, and 58 (all Ptrend < 0.001). Cumulative detection rates of CIN2+ within 10 years were predominantly contributed by HPV 16, 31, and 58. Our results support the risk-based management of HPV-positive women using HPV genotyping and also indicate the significance of including HPV 31 and 58 apart from commonly acknowledged HPV 16 and HPV 18 in achieving better risk stratification. Cancer Prev Res; 10(12); 745–51. ©2017 AACR.
Data from A Prospective Targeted Serum Metabolomics Study of Pancreatic Cancer in Postmenopausal Women
Authors: Jiao Li , Maity Suman , Coarfa Cristian , Rajapakshe Kimal , Chen Liang , Jin Feng , Putluri Vasanta , Tinker Lesley F. , Mo Qianxing , Chen Fengju , Sen Subrata , Sangi-Hyghpeykar Haleh , El-Serag Hashem B. , Putluri Nagireddy
Published: March 2024

Abstract
To examine the association between metabolic deregulation and pancreatic cancer, we conducted a two-stage case–control targeted metabolomics study using prediagnostic sera collected one year before diagnosis in the Women's Health Initiative study. We used the LC/MS to quantitate 470 metabolites in 30 matched case/control pairs. From 180 detectable metabolites, we selected 14 metabolites to be validated in additional 18 matched case/control pairs. We used the paired t test to compare the concentrations of each metabolite between cases and controls and used the log fold change (FC) to indicate the magnitude of difference. FDR adjusted q-value < 0.25 was indicated statistically significant. Logistic regression model and ROC curve analysis were used to evaluate the clinical utility of the metabolites. Among 30 case/control pairs, 1-methyl-l-tryptophan (L-1MT) was significantly lower in the cases than in the controls (log2 FC = −0.35; q-value = 0.03). The area under the ROC curve was 0.83 in the discrimination analysis based on the levels of L-1MT, acadesine, and aspartic acid. None of the metabolites was validated in additional independent 18 case/control pairs. No significant association was found between the examined metabolites and undiagnosed pancreatic cancer.
Data from Fusobacterium Nucleatum Subspecies Animalis Influences Proinflammatory Cytokine Expression and Monocyte Activation in Human Colorectal Tumors
Authors: Ye Xiangcang , Wang Rui , Bhattacharya Rajat , Boulbes Delphine R. , Fan Fan , Xia Ling , Adoni Harish , Ajami Nadim J. , Wong Matthew C. , Smith Daniel P. , Petrosino Joseph F. , Venable Susan , Qiao Wei , Baladandayuthapani Veera , Maru Dipen , Ellis Lee M.
Published: March 2024

Abstract
Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical colorectal cancer specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical colorectal cancer specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human colorectal cancers. We also assessed inflammatory cytokines in colorectal cancer specimens using immunoassays and found that expression of the cytokines IL17A and TNFα was markedly increased but IL21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 protein expression in colorectal cancer cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote colorectal cancer development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for colorectal cancer prevention and treatment. Cancer Prev Res; 10(7); 398–409. ©2017 AACR.
Data from The Effects of Physical Activity and Body Fat Mass on Colorectal Polyp Recurrence in Patients with Previous Colorectal Cancer
Authors: Park Jihye , Kim Jae Hyun , Lee Hyun Jung , Park Soo Jung , Hong Sung Pil , Cheon Jae Hee , Kim Won Ho , Park Ji Soo , Jeon Justin Y. , Kim Tae Il
Published: March 2024

Abstract
We aimed to identify the effects of physical activity and body composition on colorectal polyp recurrence in patients with previous colorectal cancer. A total of 300 patients were selected randomly from the colorectal cancer survivor cohort of Severance Hospital (Seoul, Korea). Patients reported various recreational physical activities and received surveillance colonoscopy. Body composition was measured with a body composition analyzer. We compared patients who exercised for at least 1 hour/week (active) with those who exercised less frequently or not at all (sedentary). The active exercise group (n = 203) had a lower recurrence of advanced adenoma than the sedentary group (n = 97; 6.4% vs. 14.4%, P = 0.023). The prevalence of advanced adenoma recurrence decreased in an exercise dose-dependent manner (Ptrend = 0.019). In multivariate logistic analysis, the independent factors associated with advanced polyp recurrence were body fat mass [OR, 7.601; 95% confidence interval (CI), 1.583–36.485; P = 0.011] and active exercise (OR, 0.340; 95% CI, 0.143–0.809; P = 0.015). In Cox proportional hazards models, body fat mass (HR, 5.315; 95% CI, 1.173–24.083; P = 0.030) and active exercise (HR, 0.367; 95% CI, 0.162–0.833; P = 0.017) were the independent factors associated with cumulative advanced adenoma recurrence. In conclusion, exercising for at least 1 hour/week and low body fat mass were found to be related to lower rates of colorectal polyp recurrence in the surveillance of colorectal cancer survivors. Cancer Prev Res; 10(8); 478–84. ©2017 AACR.
Data from Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo
Authors: Madka Venkateshwar , Mohammed Altaf , Li Qian , Zhang Yuting , Biddick Laura , Patlolla Jagan M.R. , Lightfoot Stan , Towner Rheal A. , Wu Xue-Ru , Steele Vernon E. , Kopelovich Levy , Rao Chinthalapally V.
Published: March 2024

Abstract
Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P < 0.0001). Similarly, CP showed approximately 77% (P < 0.0001) suppression of tumor weight. The combination of low-dose rapamycin and CP led to approximately 83% (P < 0.0001) inhibition of tumor weight. There was no significant difference in tumor weights between rapamycin and CP treatments (P > 0.05). However, there was a significant difference between 8 ppm rapamycin and the combination treatment. Tumor invasion was also significantly inhibited in 53% (P < 0.005) and 66% (P < 0.0005) mice after 8 ppm and 16 ppm rapamycin, respectively. However, tumor invasion was suppressed in 73% (P < 0.0001) mice when CP was combined with 8 ppm rapamycin. These results suggest that targeting two or more pathways achieve better treatment efficacy than a single-agent high-dose strategy that could increase the risk of side effects. A combination of CP and rapamycin may be a promising method of inhibiting muscle-invasive urothelial transitional cell carcinoma. Cancer Prev Res; 9(1); 53–62. ©2015 AACR.
Data from Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane
Authors: Bauman Julie E. , Zang Yan , Sen Malabika , Li Changyou , Wang Lin , Egner Patricia A. , Fahey Jed W. , Normolle Daniel P. , Grandis Jennifer R. , Kensler Thomas W. , Johnson Daniel E.
Published: March 2024

Abstract
Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547–57. ©2016 AACR.
Data from Gene Methylation and Cytological Atypia in Random Fine-Needle Aspirates for Assessment of Breast Cancer Risk
Authors: Stearns Vered , Fackler Mary Jo , Hafeez Sidra , Bujanda Zoila Lopez , Chatterton Robert T. , Jacobs Lisa K. , Khouri Nagi F. , Ivancic David , Kenney Kara , Shehata Christina , Jeter Stacie C. , Wolfman Judith A. , Zalles Carola M. , Huang Peng , Khan Seema A. , Sukumar Saraswati
Published: March 2024

Abstract
Methods to determine individualized breast cancer risk lack sufficient sensitivity to select women most likely to benefit from preventive strategies. Alterations in DNA methylation occur early in breast cancer. We hypothesized that cancer-specific methylation markers could enhance breast cancer risk assessment. We evaluated 380 women without a history of breast cancer. We determined their menopausal status or menstrual cycle phase, risk of developing breast cancer (Gail model), and breast density and obtained random fine-needle aspiration (rFNA) samples for assessment of cytopathology and cumulative methylation index (CMI). Eight methylated gene markers were identified through whole-genome methylation analysis and included novel and previously established breast cancer detection genes. We performed correlative and multivariate linear regression analyses to evaluate DNA methylation of a gene panel as a function of clinical factors associated with breast cancer risk. CMI and individual gene methylation were independent of age, menopausal status or menstrual phase, lifetime Gail risk score, and breast density. CMI and individual gene methylation for the eight genes increased significantly (P < 0.001) with increasing cytological atypia. The findings were verified with multivariate analyses correcting for age, log (Gail), log (percent density), rFNA cell number, and body mass index. Our results demonstrate a significant association between cytological atypia and high CMI, which does not vary with menstrual phase or menopause and is independent of Gail risk and mammographic density. Thus, CMI is an excellent candidate breast cancer risk biomarker, warranting larger prospective studies to establish its utility for cancer risk assessment. Cancer Prev Res; 9(8); 673–82. ©2016 AACR.