bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A75: Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: Biotransformation, chemical synthesis and biological evaluation
Authors: Chen Huadong , Zhu Yingdong , Soroka Dominique , Warin Renaud , Sang Shengmin
Published: January 2014

It is now well accepted that natural compounds provide the opportunity to interfere in early stages of cancer or prevent its development altogether. However, these types of compounds do have their limitations, such as short half-life and fast metabolism once ingested. Often, presence of the compound can only be assessed by quantification of metabolites, suggesting that these metabolites circulate in the body for a certain amount of time and potentially interact with biological processes. In the present study, we investigated the biotransformation of [6]-shogaol, a bioactive component in ginger (Zingiber officinale Rosc.), in cancer cells, mice and humans. Our results indicated that [6]-shogaol is extensively metabolized in cancer cells and in vivo. To further investigate whether these metabolites retain bioactivity, we synthesized the major metabolites of [6]-shogaol and evaluate their anti-cancer activities. Twelve metabolites of [6]-shogaol (M1, M2, and M4-M13) were successfully synthesized using simple and easily accessible chemical methods. Growth inhibition assays showed most metabolites of [6]-shogaol had measurable activities against human cancer cells HCT-116 and H-1299. In particular, metabolite M2 greatly retained the biological activities of [6]-shogaol. The toxicity evaluation of the synthetic metabolites (M1, M2, and M4-M13) against human normal fibroblast colon cells CCD-18Co and human normal lung cells IMR-90 demonstrated a detoxifying metabolic biotransformation of [6]-shogaol. The most active metabolite M2 had almost no toxicity to CCD-18Co and IMR-90 normal cells. TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay indicated apoptosis was triggered by metabolites M2, M13, and its two diastereomers M13-1 and M13-2. There was no significant difference between the apoptotic effect of [6]-shogaol and those of M2 and M13 at 6 hour time point treatment. (This project is supported by NIH grants CA138277 and CA138277-S1 to S. Sang).

Citation Format: Huadong Chen, Yingdong Zhu, Dominique Soroka, Renaud Warin, Shengmin Sang. Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: Biotransformation, chemical synthesis, and biological evaluation. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A75.
Abstract A76: Diet versus drug paradigm for the prevention of colorectal cancer: Isorhamnetin and resveratrol versus sulindac and DFMO
Authors: Saud Shakir , Kim Young , Bobe Gerd , Colburn Nancy H. , Young Matthew R.
Published: January 2014

Increase in polyamine synthesis and inflammation is associated with increased risk in colon carcinogenesis. In patients with a high risk for colon cancer a combination treatment with difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, and sulindac, a nonsteroidal anti-inflammatory drug, resulted in a synergistic reduction in adenoma recurrence. However, this drug combination has some toxicities and should be limited to those individuals with a positive benefit to risk ratio.

Bioactive food components have been shown to modulate inflammation and polyamine synthesis and can influence the risk of developing colon cancer with less toxicity. In this study we demonstrated that the chemopreventive activity of isorhamnetin (a plant flavonoid), and resveratrol (a naturally occurring polyphenolic compound) may mimic the effects of sulindac and DFMO. In a mouse model for colitis-associated colon carcinogenesis where mice are treated with the chemical carcinogen azoxymethane (AOM) and then exposed to colonic irritant dextran sodium sulfate (DSS), a diet enriched in isorhamnetin or resveratrol resulted in a reduction in tumor incidence by 22 and 29 percent, respectively. Furthermore, analysis of biomarkers revealed both anti-proliferative and anti-inflammatory properties of both isorhamnetin and resveratrol in vivo. More intriguingly, we found that isorhamnetin mimics sulindac activity by inhibiting Src kinase activity and interfering with Wnt/beta catenin signaling both in culture and in mice. In addition, our metabolomic analyses suggest that resveratrol mimics DFMO activity by inhibiting ornithine decarboxylase (ODC) activity in the mouse colon. Inhibition of ODC by resveratrol was confirmed in culture. It will be interesting to see if the combination of isorhamnetin and resveratrol will have a synergistic effect on prevention of colon cancer. These findings suggest that isorhamnetin and resveratrol could be used as a safer alternative to sulindac and DMFO for the prevention of colon cancer.

Citation Format: Shakir Saud, Young Kim, Gerd Bobe, Nancy H. Colburn, Matthew R. Young. Diet versus drug paradigm for the prevention of colorectal cancer: Isorhamnetin and resveratrol versus sulindac and DFMO. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A76.
Abstract A83: Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced anti-tumor activity in hypoxic PC-3 cells
Authors: Kim Sung Hoon , Lee Hyojeong , Kim Hanna Hyun , Jung Deok Beom , Sohn Eunjung
Published: January 2014

Although cryptotanshinone (CT) from Salvia miltiorrhiza Bunge was known to exert antitumor activity in liver, breast and prostate cancers, its molecular mechanism under hypoxia still remain unclear. Thus, in the present study, the roles of astrocyte elevated gene 1 (AEG-1) and HIF-1α in crytotanshinone induced antitumor activity were investigated in PC-3 prostate cancer cells under hypoxia. Cryptotanshinone exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and transcriptional activity and AEG-1 expression in hypoxic PC-3 cells. Also, AGE-1 was overexpressed in prostate cancer cells and also upregulated along with HIF-1α in hypoxic PC-3 cells. Interestingly, HIF-1α siRNA transfection blocked AEG-1 expression and activated caspase 9/3 and PARP cleavage, while AEG-1 siRNA transfection did not affect HIF-1α activity in hypoxic PC-3 cells. Of note, HIF prolyl hydroxylase inhibitor, dimethyloxalylglycine enhanced the stability of AEG-1 and HIF-1α during hypoxia. In addition, CT also significantly reduced cellular levels of VEGF, a downstream of HIF-1α, and disturbed tube formation in human umbilical vein endothelial cells maintained in conditioned medium of hypoxic PC-3 cells. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67(proliferation), CD34 (blood vessel), VEGF (angiogenesis), carbonic anhydrase(CA)IX (hypoxic marker) and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1 and VEGF as a potent chemotherapeutic agent.

Citation Format: Sung Hoon Kim, Hyojeong Lee, Hanna Hyun Kim, Deok Beom Jung, Eunjung Sohn. Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced antitumor activity in hypoxic PC-3 cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A83.
Abstract A90: The attribution of lifestyle related risk factors in middle age on breast cancer incidence in The Netherlands: Preliminary results
Authors: Gemert WAM van , Elias SG , Bausch-Goldbohm RA , Brandt PA van den , Grooters HG , Kampman E , Kiemeney LALM , Leeuwen FE van , Monninkhof EM , Vries E De , Peeters PHM
Published: January 2014

Background: Breast cancer, especially postmenopausal, is one of the most common cancers in Western women. Although therapeutic options have improved, there still is a high mortality rate. Several of the known risk factors for breast cancer are lifestyle related and modifiable, providing an opportunity for primary prevention. Middle-aged women still have the chance to modify these factors to lower nearby breast cancer risk. We estimated the fraction of postmenopausal breast cancer cases that is attributable to lifestyle factors as currently present in middle-aged Dutch women.

Methods: We estimated population attributable fractions (PAFs) of five potentially modifiable risk factors for Dutch women aged 45-54 years. Risk factors included overweight and obesity, alcohol use, physical inactivity, current use of hormone replacement therapy (HRT) and oral contraceptives.

We based relative risks on literature search including meta-analyses and expert group consensus. Current prevalence rates of the risk factors were derived from several Dutch registration databases and national surveys (2009-2011).

Results: Of all 45-54 year old contemporary Dutch women, 46% are estimated to be physically inactive, 43% to be overweight or obese, 42% to drink alcohol, 1% to use HRT and 17% to use contraceptives.

These risk factors jointly account for an estimated 20.2% of all future breast cancer cases in these women. Physical inactivity and alcohol use are responsible for the highest population attributable fraction (PAF of 7.0% and 6.8% respectively), followed by overweight and obesity (4.3%), oral contraceptive use (3.4%) and hormone replacement therapy (0.6%).

Conclusion: On a population level, lifestyle related factors play an important role in the development of postmenopausal breast cancer. Considering current prevalence rates in the Netherlands, our findings imply that modifiable risk factors present at middle-age are jointly responsible for 1 out of every 5 future breast cancer cases. This is in concordance with other studies in European countries.

Our findings thus suggest that incidence rates can be lowered substantially by changing lifestyle habits, even in a woman's later life.

Citation Format: WAM van Gemert, SG Elias, RA Bausch-Goldbohm, PA van den Brandt, HG Grooters, E Kampman, LALM Kiemeney, FE van Leeuwen, EM Monninkhof, E De Vries, PHM Peeters. The attribution of lifestyle related risk factors in middle age on breast cancer incidence in The Netherlands: Preliminary results. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A90.
Abstract A93: Genetic variations in aging related genes/pathways and colorectal cancer risk
Authors: Zhang Fanmao , Eng Cathy , Lin Moubin , Hildebrandt Michelle A.T. , He Yonggang , Lin Jie , Huang Maosheng , Gu Jian , Wu Xifeng
Published: January 2014

Advanced age is arguably the most important risk factor for developing cancer. About 77% of all cancers are diagnosed in individuals 55 years of age and older. Aging is especially a dominant risk factor for colorectal cancer (CRC), with 91% of cases diagnosed in individuals 50 years of age and older. A number of genes and signaling pathways have been indicated in the aging process in model organisms including mammals, e.g. the insulin/IGF-1 signaling pathway, mTOR pathway and telomere and telomerase pathway. Recently, genome-wide association studies also identified several single nucleotide polymorphisms (SNPs) associated with longevity. Therefore, we hypothesized that genetic variations of the genes and pathways related to aging might be associated with CRC risk. We systematically identified 189 putative functional SNPs in 109 aging-related genes and 20 longevity-associated SNPs from GWAS. In the discovery phase, we genotyped these SNPs in 797 Caucasian CRC cases and 797 matched healthy control subjects. In main effect analysis, 10 SNPs were significantly associated with altered CRC risk. When evaluating combined effects of these SNPs, we found a significant gene dosage effect for increased CRC risk with increasing number of unfavorable genotypes. Compared with individuals carrying fewer than three unfavorable genotypes, individuals with six and more than six of these unfavorable genotypes exhibited a 2.06-fold (95% CI: 1.24-3.43, P = 0.006) and a 2.44-fold (95% CI: 1.76-3.38, P = 7.56×10−8) increased risk of CRC, respectively (P for trend 1.25×10−9). Higher order gene-gene interaction analysis also revealed potential relationships among SNPs in TP53, ERCC2, GPR133, PRKAG3, TEP1, TSC1 and LMNA that further defined risk groups for CRC. Our results suggest that genetic polymorphisms in aging-related genes and pathways may modify CRC susceptibility both individually and jointly. Replication is currently underway to validate these findings.

Citation Format: Fanmao Zhang, Cathy Eng, Moubin Lin, Michelle A.T. Hildebrandt, Yonggang He, Jie Lin, Maosheng Huang, Jian Gu, Xifeng Wu. Genetic variations in aging-related genes/pathways and colorectal cancer risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A93.
Abstract A94: Missed opportunities: Racial and socioeconomic disparities in emergency presentation of colorectal cancer
Authors: Pruitt Sandi L. , Davidson Nicholas O. , Gupta Samir , Yan Yan , Schootman Mario
Published: January 2014

Background: Emergency presentation for colorectal cancer (CRC) is common and associated with high morbidity and mortality. African Americans and those with lower socioeconomic status (SES) experience higher CRC morbidity and mortality, and higher rates of emergency CRC presentation may, in part, account for these disparities. We hypothesized that African Americans and individuals with low SES have higher rates of emergency CRC presentation.

Methods: We examined disparities in emergency CRC presentation using nationally representative 1992-2005 SEER-Medicare data of U.S. adults aged ≥66 years with invasive CRC. Emergency CRC presentation (the primary outcome) was defined as a newly diagnosed CRC associated with: obstruction, perforation, or an inpatient admission requiring immediate medical intervention (e.g. for severe, life threatening conditions) identified using Medicare claims with ICD-9 and admission type codes. We used logistic regression to compare associations of race and census tract poverty rate with emergency CRC presentation, adjusting for sociodemographic (age, sex, Medicaid status, year of diagnosis, urban/rural residence at diagnosis), tumor (SEER historic stage, left/right side tumor location, grade, histology), and clinical (history of the following in the prior year: preventable hospitalizations, comorbidity, endoscopic testing) covariates.

Results: We identified 88,859 patients with CRC during the study period, 29.0% of whom presented emergently (of these, 81.3% had an emergency admission, 31.6% obstruction, and 4.2% perforation). In unadjusted analyses, CRC patients more likely to present emergently included African Americans (vs. whites OR: 1.64 95% CI: 1.57-1.72) and those living in census tracts with the highest poverty rate (≥20% vs. <10% poverty OR: 1.31 95% CI: 1.26-1.37). In a single multivariable model, after adjusting for all covariates including tumor stage, African Americans (vs. whites AOR: 1.29 95% CI: 1.21-1.37) and those living in census tracts with the highest poverty rate (≥20% vs. <10% poverty AOR: 1.10 95% CI: 1.04-1.16) continued to be more likely to present emergently.

Discussion: In this population-based study, racial and socioeconomic disparities are evident in emergency presentation of CRC, which may account for some of the observed disparities in morbidity and mortality. Targeted efforts to increase CRC screening in these populations would reduce this preventable disparity.

Citation Format: Sandi L. Pruitt, Nicholas O. Davidson, Samir Gupta, Yan Yan, Mario Schootman. Missed opportunities: Racial and socioeconomic disparities in emergency presentation of colorectal cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A94.
Abstract A99: Dietary N-nitroso compounds, endogenous nitrosation and the risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study
Authors: Keszei András P. , Goldbohm R Alexandra , Schouten Leo J. , Jakszyn Paula , Brandt Piet A. van den
Published: January 2014

Background: Dietary N-nitroso compounds and endogenous nitrosation are important carcinogenic factors, but evidence for their role from population studies is scarce for esophageal, and inconsistent for gastric cancer.

Objective: We studied the relationship between the risk of esophageal and gastric cancer subtypes and dietary intake of N-nitrosodimethylamine, heme iron, nitrite and nitrate in The Netherlands Cohort Study.

Methods: 120 852 men and women aged 55-69 years were recruited in 1986, and diet, based on a 150-item food frequency questionnaire, as well as other risk factors were assessed. The cohort was followed for 16.3 years, and 110 esophageal squamous cell carcinomas, 151 esophageal adenocarcinomas, 166 gastric cardia adenocarcinomas, and 497 gastric non-cardia adenocarcinoma cases were analyzed along with 4032 subcohort members in a case-cohort analysis.

Results: There were positive associations between N-nitrosodimethylamine intake and esophageal squamous cell carcinoma and gastric non-cardia adenocarcinoma risk in men (hazard ratio (HR) for 0.1 μg/day increase in intake: 1.15 [95% confidence interval (CI): 1.05-1.25; P(trend): 0.01] and 1.06 [95%CI: 1.01-1.10; P(trend): 0.09], respectively). Esophageal squamous cell carcinoma risk was associated with nitrite and heme iron intake (HR for 0.1 mg/day increase in nitrite intake: 1.19 [95%CI: 1.05-1.36; P(trend): 0.06] and for 1 mg/day heme iron intake: 1.83 [95%CI: 0.98-3.39; P(trend): 0.03]). Among women, exposure levels were lower, and we found a positive association only between N-nitrosodimethylamine and esophageal squamous cell carcinoma risk (HR for 0.1 μg/day increase: 1.34 [95%CI: 1.04,1.71; P(trend):0.57]).

Conclusion: These results suggest that N-nitroso compounds and their precursors may influence the risk of esophageal squamous cell carcinoma.

Citation Format: András P. Keszei, R Alexandra Goldbohm, Leo J. Schouten, Paula Jakszyn, Piet A. van den Brandt. Dietary N-nitroso compounds, endogenous nitrosation, and the risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A99.
Abstract B08: Effectiveness of team-based financial incentives for smoking cessation in the workplace
Authors: Haak Lee Sang , Dong Yeo Chang , Kyoung Kim In , Sun Kang Hye , Young Lee Hwa , Kwon Park Chan , Sook Kim Myung
Published: January 2014

Objective: Workplace offers a promising venue for encouraging smoking cessation. Worksite smoking cessation programs offer a number of advantages, including the accessibility of the target population, the availability of occupational health support and the potential for peer pressure and peer support. Financial incentives given to teams rather than individual participants could create team based effort to support and reinforce smoking cessation within the workplace. The purpose of this study is to identify the effectiveness of team-based financial incentives in improving long-term rates of smoking cessation among employees.

Methods: Total 28 smokers who were healthcare workers from St. Paul's Hospital, were enrolled. The financial incentives were ₩50,000 for smoking cessation at 1 week and 1 month after the initial cessation and ₩100,000 for abstinence at 3 and 6 months after the initial cessation.

Results: Abstinence rate at 3, 6 and 12 months after the initial cessation were 61%, 54% and 50%, respectively. There were no differences in age, body mass indexes and spirometric indexes between the success and failure group. Nicotine dependence scores were significantly higher in the failure group at 3 months, but not at 6 and 12 months. Smokers who participated within 1 month of enrollment had a higher abstinence rate at 3 months than those who participated after 1 month (p=0.007).

Conclusion: Team based financial incentives resulted in high abstinence rates, which was maintained through 12 months. These results suggest that the financial incentives given to teams could make use of the potential for peer pressure and peer support over a longer period. In addition, more intensive management is needed to members who participate after 1 month and have higher nicotine dependence scores, which results in a lower abstinence rate.

Citation Format: Lee Sang Haak, Yeo Chang Dong, Kim In Kyoung, Kang Hye Sun, Lee Hwa Young, Park Chan Kwon, Kim Myung Sook. Effectiveness of team-based financial incentives for smoking cessation in the workplace. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B08.
Abstract B09: PROMOTER CPG ISLAND METHYLATION DURING PROGRESSION OF ATYPICAL HYPERPLASIA TO BREAST CANCER
Authors: Martinez-Galan Joaquina , Delgado Juan Ramon , Moral Rosario Del , Torres-Torres Blanca
Published: January 2014

DNA methylation is the main epigenetic modification in cancer. The pathological features of breast cancer follow a sequential progression from transition of a normal cell to benign proliferative hyperplasia, hyperplasia with atypia, in situ carcinoma and, eventually, to invasive and metastatic disease. Purpose: This study was designed to evaluate the changes in promoter CpG islands hypermethylation during breast cancer progression from pre-invasive lesions to invasive ductal carcinoma and different methylation patron with benign breast disease. Material and Methods: We performed analysis for the methylation status of 5 promoter CpG island (ESR1, E-Cad, APC, RARB and 14-3-3-σ promoters) in a group with women with normal breast tissue n=74; other group with epithelial atypia/ atypical ductal hyperplasia (n=20), ductal carcinoma in situ (DCIS, n=14) and invasive ductal carcinoma (IDC, n=107). Results:Relative serum levels of methylated gene promoters ESR1 and 14-3-3-σ showed significant differences between IDC y normal breast tissue (were significantly higher in IDC than normal breast tissue) and between normal breast tissue and epithelial atypia/ atypical ductal hyperplasia/ ductal carcinoma in situ. There are no differences between IDC and epithelial atypia/ atypical ductal hyperplasia/ ductal carcinoma in situ when 14-3-3-σ and ESR1 mean values are compared. In fact, the present findings showed a frequent presence of methylated 14-3-3-σ in sera from women with breast benign disease, which could be considered the result of a proliferative alteration of epithelial and stromal components of the breast. Which may indicate presence of occult benign breast disease, although other possible sources of this DNA include normal tissues, which show higher methylation values with increasing age; which might undergo lysis during tumour growth; or premalignant lesion during tumour growth; or premalignant lesion.

Conclusions: These findings showed that promoter CpG island methylation changed significantly in pre-invasive lesions, and breast cancer, suggesting that CpG island methylation of tumor-related genes is an early event in breast cancer progression.

Citation Format: Joaquina Martinez-Galan, Juan Ramon Delgado, Rosario Del Moral, Blanca Torres-Torres. Promoter CpG island methylation during progression of atypical hyperplasia to breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B09.
Abstract B10: Design of the DENSE trial: MRI as an additional screening modality to detect breast cancer in women aged 50-75 years with extremely dense breasts
Authors: Emaus Marleen , Veldhuis Wouter , Bakker Marije , Monninkhof Evelyn , Karssemeijer Nico , Bosch Maurice van den , Peeters Petra , Mali Willem , Gils Carla van
Published: January 2014

Background: Women with high mammographic density have an increased breast cancer risk and also a lower mammographic tumor detectability. Nevertheless, these women are currently screened with mammography only. MRI could lead to earlier tumor detection, because of its higher sensitivity. To study the additional value of MRI, a parallel-group randomized controlled trial design is needed with one group receiving mammography and the other group receiving mammography and MRI. With this design it is possible to determine the proportion of interval tumors within each arm. A reduction in interval tumors is a precondition of effectiveness, because this represents clinically relevant cancer detection, rather than overdiagnosis.

Study design: DENSE is a multicenter randomized trial, carried out in the Dutch biennial screening program (age range 50-75 years). Mammographic density is measured using a fully-automated volumetric method (Volpara™). Participants with extremely dense breasts (ACR4) and a negative mammogram are randomized to ‘additional MRI’ (n=7,237) versus ‘current practice’ (n=28,948). After randomization, only the intervention arm is asked for consent (single-consent prerandomized design). The intervention consists of a dynamic breast MRI with gadolinium-based contrast medium (Gadovist®) and is carried out for 3 screening rounds. The primary outcome is the difference in proportion of interval tumors between the arms. Secondary outcomes are the number of MRI screen-detected tumors, proportion false-positives, quality of life, breast cancer mortality and costs.

Conclusion: DENSE investigates the (cost-)effectiveness of screening with mammography and MRI compared to mammography alone in women with extremely dense breasts aged 50-75 years. Inclusion started in December 2011.

Citation Format: Marleen Emaus, Wouter Veldhuis, Marije Bakker, Evelyn Monninkhof, Nico Karssemeijer, Maurice van den Bosch, Petra Peeters, Willem Mali, Carla van Gils. Design of the DENSE trial: MRI as an additional screening modality to detect breast cancer in women aged 50-75 years with extremely dense breasts. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B10.
Abstract B104: Expressions of PCNA in triple negative breast cancers and Their clinical significance
Authors: Jiaping Peng , qun meng
Published: January 2014

Objective: To study expressions of matrix metalloproteinase-13 (PCNA) in triple negative (ER-, PR-, HER2-) breast cancers and evaluate their clinical significance.

Methods: The immunohistochemistry SP method was used to evaluate the expressions of PCNA in 32 cases of triple negative breast cancers, 24 cases of HR breast cancer (ER+/PR+, HER-2-), 12 cases of HER2 breast cancer (ER-, PR-, HER2+) and 12 cases of breast fibroadenoma and their correlations to clinicopathologic features were analyzed.

Results: The expressions of PCNA were significantly higher in the triple negative breast cancers than in breast fibroadenoma and HR breast cancers (P<0.05). Furthermore, the expression of PCNA was significantly higher in the triple negative breast cancers than in HER2 breast cancers (P <0.05). In the triple negative breast cancers, PCNA expression was associated with axillary lymph node metastasis and TNM stage (P <0.05), but it was not correlated with patients age (P >0.05). Correlation analysis showed that PCNA expression was positively correlated in the triple negative breast can cers, HR breast cancers and HER2 breast cancers (P <0.05).

Conclusion: There is a close relationship between PCNA the occurrence and development of triple negative breast cancers, and PCNA could serve as important indexes in the aspect of invasiveness and metastasis in triple negative breast cancers.

Citation Format: Peng Jiaping, meng qun. Expressions of PCNA in triple-negative breast cancers and their clinical significance. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B104.
Abstract B113: High Fat Diet Accelerates Development of Precancerous Lesions and Fibrosis in Mice Expressing mutant K-Ras in Pancreatic Acinar Cells
Authors: Cruz-Monserrate Zobeida , Philips Bincy , Ji Baoan , Daniluk Jaroslaw , Logsdon Craig D.
Published: January 2014

Background: Obesity is postulated to be a major risk factor for pancreatic ductal carcinoma (PDAC), which is the fourth deadliest cancer in the US. Although the association between obesity and pancreatic cancer has been reported, the molecular mechanisms are not yet known. Since K-Ras mutations are almost universal in PDAC, and we have recently shown that endogenous levels of oncogenic K-Ras make cells susceptible to otherwise benign levels of inflammation, we hypothesize that high fat intake can act as a persistent low level inflammatory mechanism capable of inducing PDAC in cells expressing a single copy of oncogenic K-Ras. In the current study, we examined the effects of high dietary fat on the development of precancerous lesions and fibrosis, as well as the activation of K-Ras signaling pathways in mice expressing mutant K-Ras in pancreatic acinar cells.

Methods: Transgenic mice LSL-K-Ras were cross with Ela-CreER (Pancreatic-Ras) and treated with tamoxifen to “knock-in” oncogenic K-Ras in adult pancreatic acinar cells. Pancreatic-Ras and littermate control mice were administered a low fat diet with 10.2% kcal fat or a high fat diet with 61.6% kcal fat for 30 days starting at 50 days of age. Mice were then sacrificed and analyzed histologically for fibrosis development, presence of precancerous lesions, and activation of K-Ras signaling pathways.

Results: Mice expressing endogenous levels of oncogenic K-Ras and fed a high fat diet developed abundant fibrosis, low grade precancerous lesions throughout the pancreas and had higher levels of phospho-ERK when compared to littermate controls and mice fed a low fat diet.

Conclusions: These findings suggest that consumption of high dietary fat acts as an inflammatory stimulus that enhances the activation of oncogenic K-Ras downstream signaling pathways, leading to the early development of precancerous lesions and fibrosis in the pancreas. Therefore, efforts aimed at inhibiting inflammation and K-Ras activation would be expected to prevent cancer development.

Citation Format: Zobeida Cruz-Monserrate, Bincy Philips, Baoan Ji, Jaroslaw Daniluk, Craig D. Logsdon. High-fat diet accelerates development of precancerous lesions and fibrosis in mice expressing mutant K-Ras in pancreatic acinar cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B113.
Abstract B22: Molecular oncogenesis of NANOG in castration-resistant prostate cancer
Authors: Jeter Collene R. , Lu Yue , Liu Bigang , Gaddis Sally , Liang Shoudan , Tang Dean G.
Published: January 2014

Regardless of the cell-of-origin, self-renewing tumor cells may be a driving force in cancer progression to lethal disease. An important outstanding question in the field of oncology is by what molecular mechanisms do tumor cells acquire stem cell (SC) biological properties? The embryonic stem cell pluripotency molecule NANOG appears to be among the important SC-related self-renewal genes underlying molecular oncogenesis. We have previously reported that NANOG attenuation inhibited prostate cancer cell clonogenic growth and in vivo tumorigenicity. Subsequently, we have found that NANOG overexpression in LNCaP prostate cancer cells promoted clonogenicity and tumor development particularly in androgen-deprived conditions. Furthermore, NANOG knockdown in relatively undifferentiated PSA- prostate cancer cells significantly reduced tumor regeneration in castrated hosts implicating NANOG in the emergence of castration-resistant prostate cancer (CRPC). To understand the molecular underpinnings of NANOG-mediated CRPC, we have performed ChIP-Seq analysis of NANOG occupancy in LNCaP cells overexpressing NANOGP8 or NANOG1. These non-biased and global studies have revealed downstream genes and signaling pathways that may potentially be regulated by NANOG in cancer cells and shed light on the NANOG castration-resistance phenotype. ∼60% of the promoter occupied sites are shared between NANOGP8 and NANOG1, representing 806 genes. Among these are many developmental-associated genes, chromatin remodeling and epigenetic regulators and molecules implicated in prostate cancer. In addition, motif analysis of NANOG occupied regions has revealed a novel candidate NANOG-interacting protein in prostate cancer cells. Integration of ChIP-Seq data with RNA-Seq is currently underway and integrative analysis is anticipated to further discriminate the direct and indirect molecular architecture responding to NANOG expression in prostate cancer.

Citation Format: Collene R. Jeter, Yue Lu, Bigang Liu, Sally Gaddis, Shoudan Liang, Dean G. Tang. Molecular oncogenesis of NANOG in castration-resistant prostate cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B22.
Abstract B36: Transcriptional targeting of tumor cells with AAV vectors carrying diphtheria toxin A fragment
Authors: Chen Haifeng
Published: January 2014

Suicide gene therapy is an attractive way of combating cancers. Diphtheria toxin (DT) has been widely studied for its application to kill cancer cells. Due to DT's extreme toxicity issue, viral vectors carrying DT are very difficult to produce since producer cells are killed before viral vectors can be produced. In this study adeno-associated viral (AAV) vectors carrying DT fragment A (DT-A) was generated at high titers in insect cells by inserting a mammalian intron to abolish the toxin expression. When these toxin carrying AAV vectors were introduced into mammalian cells, the intron was spliced out and the toxin expressed and killed the mammalian cells. Since they can direct gene expression in tumor cells but not in normal cells, tumor-specific promoters were cloned to direct the expression of the DT-A gene and AAV vectors were prepared. These vectors carrying DT-A under control of surviving or CXCR4 promoter specifically killed tumor cell lines HepG2, Hep3B, and BE (2)-M17, but not the normal human lung cell line WI38. The results in this study indicate that this novel way of targeting tumor cells with AAV vectors carrying DT-A should provide a new tool for the development of toxin-based suicide gene therapy drugs.

Citation Format: Haifeng Chen. Transcriptional targeting of tumor cells with AAV vectors carrying diphtheria toxin A fragment. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B36.
Abstract B38: Iodine supplement exerts antineoplastic adjuvancy, chemoresistance inhibition and cardioprotection in mammary cancer treatment with anthracyclines
Authors: Aceves Carmen , Alfaro-Hernandez Yunuen , Delgado Guadalupe
Published: January 2014

Mortality for mammary cancer (MC) has decreased in the past decade, owing principally to early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause regression of MC, Doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use has been limited due to the rapid development of chemoresistance and cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with moderately high doses of molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced MC models. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. In the present study we analyzed the effect of I2 in combination with DOX treatment. Female Sprague Dawley rats with MNU-induced MC were treated with the therapeutic DOX dose (16 mg/kg) and with two lower doses (8 and 4 mg/kg) with and without 0.05% I2 in drinking water. In a first, short-term experiment, iodine treatment began 2 days before a single DOX injection (ip), and the animals were analyzed after 7 days. In a second experiment, animals received two injections (days zero and 14) of 4 mg/kg DOX without or with long-term I2 treatment throughout the 56 days of observation. The results showed that at every DOX dose, short-term I2 treatment induced synergic antineoplastic effects (decreasing tumor size and PCNA signal) with significant protection against body weight loss and cardiotoxicity (CK-MB enzyme and cardiac lipoperoxidation). With long-term I2 treatment, mammary tumors became more sensitive to 4 mg/kg DOX, decreasing chemoresistance markers (Bcl2 and survivin) and increasing peroxisome proliferator-activated receptor type gamma expression, indicating a specific interaction of I2 with these receptors.

The authors thank Felipe Ortóz for his technical assistance and Leonor Casanova for academic supports. Supported in part by PAPIIT/UNAM 201210 and CONACYT 78955.

Citation Format: Carmen Aceves, Yunuen Alfaro-Hernandez, Guadalupe Delgado. Iodine supplement exerts antineoplastic adjuvancy, chemoresistance inhibition and cardioprotection in mammary cancer treatment with anthracyclines. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B38.
Abstract B43: Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice.
Authors: Guillermo Ruth F. , Zhang Xiaoying , Kaushik Radhey S. , Zeman David , Ahmed Safwat A. , Khalifa Sherief , Fahmy Hesham , Dwivedi Chandradhar
Published: January 2014

Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm2 UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm2. This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into 5 groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 hour before UVB radiation (30 mJ/cm2). The last group of animals received 60 μg SD/200 μl acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were closely monitored as well. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment.

The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose, reflected in reduced tumor multiplicities and tumor volumes. SD also reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD applications without UVB exposure had no effect on the structure of mice skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

Citation Format: Ruth F. Guillermo, Xiaoying Zhang, Radhey S. Kaushik, David Zeman, Safwat A. Ahmed, Sherief Khalifa, Hesham Fahmy, Chandradhar Dwivedi. Dose-response on the chemo-preventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B43.
Abstract B53: Triterpene Fraction of Cucumis trigonus - A Novel Microtubule Inhibitor and Antitumor Agent, Induce Cell Death in Cancer Cells.
Authors: Patel Viralkumar Laxmanbhai , Wadhwani Ashish D. , P. Vijayan
Published: January 2014

Taxol-based combination chemotherapy remains the predominant treatment for cancer. However, taxane related drug resistance and neurotoxicity have promoted us to develop substitute treatment strategies. Kinesis spindle protein which is crucial for bipolar spindal formation and duplicate chromosome separation in early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The Aim of study was to investigate the mechanism of inhibition of kinesis spindle protein that plays an essential role in establishing mitotic spindle bipolarity, by the novel small molecular inhibitor.

Antiproliferative activity of triterpene fraction of cucumis trigonus(TF25CT) in cancer cell line was accessed by cell viability assay (MTT and SRB). TF25CT showed dose dependent inhibition of cell proliferation of cancer cells. The antiproliferative effect of TF25CT was also associated with induction of apoptosis as well as morphology changes and DNA fragment. The morphology of Apoptosis nuclei was quantified using Hoechst stating and PI fragmentation. The degree of DNA fragmentation was analyzed by using agarose gel electrophoresis. The observations indicate that induced apoptotic- liked in morphological changes such as cell shrinkage and blebbing. Suppression of microtubule dynamics is responsible for the ability of TF25CT to inhibit the mitotic progression and cell proliferation using fluorescent microscope, we examined the effect of TF25CT on dynamics of individual microtubule in two living human cancer cell line. Taken together the kinesis protein inhibitor represents an imported compound for further investigate as novel anticancer therapeutics.

Citation Format: Viralkumar Laxmanbhai Patel, Ashish D. Wadhwani, Vijayan P. Triterpene fraction of Cucumis trigonus, a novel microtubule inhibitor and antitumor agent, induces cell death in cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B53.
Abstract B57: STAT3 as a cancer prevention target in colorectal cancer cells
Authors: Lin Li , Yu Wenying , Xiao Hui , Wang Wenlong , Zhao Chongqiang , Lu Jiagao , Li Chenglong , Lin Jiayuh
Published: January 2014

Colorectal cancer is the third most frequently occurring cancer in both men and women and is the second leading cause of cancer deaths in the United States. Despite advances in the treatment of this cancer, the five-year averaged survival rate for all stages has only increased to 66% and more than 49,000 deaths of colon cancer in the United States in 2011. Hence, novel therapeutic approaches of more effective treatments are much needed for colon cancer. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in human cancer including colon cancer, and has emerged as an attractive molecular target for cancer prevention and therapy. We tested the efficacy of inhibiting persistent STAT3 signaling by a dietary agent, Ursolic acid from basil and a novel STAT3-selective inhibitor, LY5 in human colon cancer cell lines. Our data demonstrated that Ursolic acid is able to inhibit STAT3 phosphorylation, and induce apoptosis in HCT116 and SW480 human colon cancer cell lines. These results were confirmed by LY5, a novel STAT3-selective small molecular inhibitor, which also inhibits STAT3 phosphorylation and induces apoptosis in HCT116 and SW480 colon cancer cell lines. In addition, LY5 inhibits IL-6 mediated induction of STAT3 phosphorylation in DLD-1 human colon cancer cells. We also found Ursolic acid decrease cell viability and inhibit the tumorsphere formation of ALDH+/CD133+ colon cancer stem cells. Furthermore, administration daily of Ursolic acid suppressed the HCT116 tumor growth in mice in vivo. In summary, our results suggest that STAT3 is target for colon cancer prevention and inhibition of persistently activated STAT3 using dietary agents or inhibitors may offer an effective prevention approach for colorectal carcinoma.

Citation Format: Li Lin, Wenying Yu, Hui Xiao, Wenlong Wang, Chongqiang Zhao, Jiagao Lu, Chenglong Li, Jiayuh Lin. STAT3 as a cancer prevention target in colorectal cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B57.