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Supplement: International Research Conference on Food, Nutrition, and Cancer

Poster Abstracts¹

	Angiogenesis

TOP Angiogenesis Apoptosis Biomarkers Food Composition Dietary Pattern and Cancer... Calorie Restriction Obesity Survivorship Colorectal Cancer Breast Cancer Prostate Cancer Herbs Soy Phytochemicals Lipids Vitamins Minerals

 
Se-(Methyl)selenocysteine Causes Tumor Vessel Maturation Leading to Synergistic Antitumor Effect in Human Xenografts. Arup Bhattacharya,¹ Károly Tóth,¹ Shousong Cao,¹ Rami G. Azrak,¹ Farukh A. Durrani,¹ Youcef M. Rustum,¹ and Lakshmi Pendyala.² Departments of ¹Cancer Biology and ²Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Pretreatment with 5-methylselenocysteine (MSC) before chemotherapy leads to synergistic chemomodulation with a wide range of anticancer drugs including taxanes, taxols, fluoropyrimidines, irinotecan (CPT-11), platinum compounds, and cyclophosphamide. This synergy is neither drug, tumor, nor host specific and was not seen in vitro. MSC down-regulates vascular endothelial growth factor, cyclooxygenase-2, inducible nitric oxide synthase, hypoxia-inducible factor-1, and prostaglandin E₂ in tumors, leading to an antiangiogenic effect. The hallmarks of tumor vasculature lacking smooth muscle and pericytes are that they are leaky; are chaotic; and shut off and on intermittently, imparting a tortuous tumor blood flow and distribution. The resultant adverse intratumoral interstitial fluid pressure retards intratumoral drug delivery and distribution. Studies were performed using female athymic nude mice bearing different xenografts that were treated daily for up to 14 d with MSC at 0.2 mg/d p.o. to determine whether antiangiogenic effects of MSC involve tumor vessel maturation and whether vessel maturation leads to higher intratumoral drug delivery, leading in turn to better therapeutic synergy. Immunohistochemical study for vessel maturation used CD31 and -smooth muscle actin double staining on frozen tumor sections. Immunofluorescence evaluation for vessel functionality used mice bearing tumors that were injected i.v. with Hoechst 33342 in sterile phosphate-buffered saline at 15 mg/kg and 20 min later with DiOC₇ dissolved in DMSO at 1 mg/kg; tumors were harvested after 5 min. Vessel lumen areas were measured using CD31 immunostaining. After MSC therapy, the xenografts demonstrated tumor vessel maturation, as indicated by increased pericyte coverage and uptake of both fluorescent dye, and a reduced vessel lumen area compared with untreated tumors (146 vs. 82 µm in FaDu and 66 vs. 32 µm in A253; P < 0.0001). Thus, antiangiogenic MSC leads to tumor vessel maturation and results in higher intratumoral drug delivery (CPT-11, doxorubicin) without any risk of additive host tissue toxicity. Better drug delivery leads to better therapeutic efficacy.

Sulforaphane Suppresses Angiogenesis and Disrupts Endothelial Mitotic Progression and Microtubule Polymerization. Steven J.T. Jackson,¹ Keith W. Singletary,² and Richard C. Venema.^{1 1}Vascular Biology Center, Medical College of Georgia, Augusta, GA; and ²Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL.

Sulforaphane (SUL), an isothiocyanate derived from broccoli and other cruciferous vegetables, induces phase II detoxification enzymes, disrupts cancer cell microtubule polymerization, and triggers cell cycle arrest in breast and colon cancer cells. Here, we provide the first evidence that SUL also inhibits angiogenesis via suppression of endothelial cell proliferation. Bovine aortic endothelial (BAE) cells were exposed to concentrations of SUL up to 15 µmol/L before cell cycle analysis and mitotic index quantification. Within 24 h, 15 µmol/L of SUL clearly induced G₂/M accumulation and premetaphase arrest in BAE cells. Moreover, immunofluorescence tubulin staining indicated that this same SUL concentration not only disrupted mitotic progression but also perturbed normal polymerization of mitotic (and cytoplasmic) microtubules. Furthermore, daily administration of SUL (100 nmol/d, i.v. for 7 d) to female BALB/c mice bearing VEGF-impregnated Matrigel plugs strongly and significantly (P < 0.05) suppressed angiogenesis progression as measured by hemoglobin concentration. Taken together, these findings suggest that the endothelial cell population is a novel target of sulforaphane action both in vitro and in vivo. This mechanism of SUL-induced endothelial microtubule disruption and early mitotic arrest may further discern a potential role of SUL as a chemopreventive agent.

In Vivo Imaging and Characterization of Hypoxia-Induced Neovascularization and Tumor Invasion. Gina F. Lungu,¹ Meng-Lin Li,² Xueyi Xie,¹ Lihong V. Wang,² and George Stoica.^{1 1}Department of Pathobiology, College of Veterinary Medicine, and ²Optical Imaging Laboratory, Department of Biomedical Engineering, Texas A&M University, College Station, TX.

A diet rich in fruits, vegetables, and other plant foods may reduce the risk of cancer, but few links to cancer have been established. Finding a method to determine the effect of dietary compounds on cancer and to monitor the disease progression will be of interest. This study provides an integrated approach to define oxygen status (hypoxia) of intracranial tumor xenograft using a novel spectroscopic photoacoustic tomography technology (SPAT). This approach is supported by our molecular biology investigation. Brain tumors can be identified by their distorted vascular architecture and oxygen saturation images. Noninvasive in vivo tumor oxygenation imaging using SPAT is based on the spectroscopic absorption differences between oxyhemoglobin and deoxyhemoglobin. Sprague-Dawley rats inoculated intracranially with ENU1564, a carcinogen-induced rat mammary adenocarcinoma cell line, were imaged with SPAT 3 wk postinoculation. Proteins important in tumor hypoxia and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with normal brain. Immunohistochemistry, Western blotting, and semiquantitative RT-PCR showed that hypoxia-inducible factor-, vascular endothelial growth factor-A, and vascular endothelial growth factor-R2 protein and mRNA expression levels were significantly higher (P < 0.05) in brain tumor tissues than in normal brain. Gelatin zymography and RT-PCR demonstrated the up-regulation of matrix metallopeptidase-9 in tumor foci compared with normal brain. Together these results suggest the critical role of hypoxia in driving tumor angiogenesis and invasion through up-regulation of target genes important for these functions. Moreover, this report validates our hypothesis that SPAT is suitable for detecting tumors, hypoxia, and angiogenesis and for monitoring a cell-targeted therapeutic approach to brain malignancies. We hope that SPAT will be used in the near future to monitor the effect of different dietary compounds on brain malignancy.

	Apoptosis

TOP Angiogenesis Apoptosis Biomarkers Food Composition Dietary Pattern and Cancer... Calorie Restriction Obesity Survivorship Colorectal Cancer Breast Cancer Prostate Cancer Herbs Soy Phytochemicals Lipids Vitamins Minerals

 
Inhibition of Na⁺/K⁺-ATPase by Ouabain Potentiates Apoptosis by Inducing Perturbations in Cell Calcium Homeostasis: A Protective Role Selective for Bcl-2. Michail Panagiotidis and John A. Cidlowski. Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Apoptosis is a well-defined programmed process with distinctive characteristics including cellular shrinking, chromatin condensation, and formation of membrane-bound apoptotic bodies. Cell shrinkage occurs early in apoptosis and is accompanied by changes in the activity of ion channels and plasma membrane transporters. Na⁺/K⁺-ATPase couples the energy released from the hydrolysis of ATP to the transport of Na⁺ and K⁺ ions, thus controlling cell volume and plasma membrane potential. Additionally, the Na⁺/K⁺-ATPase is the only known receptor for cardiac glycosides including ouabain. We hypothesize that Na⁺/K⁺-ATPase is essential in modulating apoptosis, and thus, its inhibition with ouabain should potentiate the apoptotic process. We report that ouabain potentiated apoptosis in wild-type Jurkat cells exposed to Fas ligand (FasL) by increasing the percentage of shrunken cells, percentage of degraded DNA content, and caspase 3/7-like activity. When cells were treated with ouabain and then exposed to other apoptotic agents [H₂O₂, staurosporine, TNF-related apoptosis-inducing ligand (TRAIL), thapsigargin], only exposure to TRAIL showed potentiation of apoptosis, indicating that such potentiation is restricted to the death receptor pathway (FasL and TRAIL). In addition, we observed that ouabain induced perturbations in cell calcium homeostasis on both FasL and TRAIL treatments. Ouabain-induced potentiation of apoptosis was abolished in Bcl-2–overexpressing cells by inhibiting perturbations in cell calcium homeostasis, whereas Bcl-X_L overexpression had no effect. To conclude, our data indicate a novel role for calcium in modulating ouabain-induced potentiation of apoptosis and that Bcl-2 selectively modulates calcium homeostasis.

Alterations in Cellular Levels of Inositol Polyphosphates during Apoptosis. Rakhee Agarwal, Aparna Konidala, and Nawab Ali. Graduate Institute of Technology, University of Arkansas at Little Rock, Little Rock, AR.

Inositol polyphosphates (InsPs) regulate diverse cellular processes including calcium homeostasis, vesicular trafficking, chromatin remodeling, and nuclear export of mRNA. Exogenous InsPs inhibit cellular growth by inducing apoptosis in certain cancer cell lines, perhaps by interfering with the pleckstrin homology domain of the phosphatidylinositol 3-kinase, and thus have potential as anticancer agents. However, whether exogenous InsPs enter the intact cells is debatable. Changes in cellular levels of InsPs may bring about apoptotic changes; higher InsP levels increased during apoptosis. We examined apoptosis induced by InsPs in mouse osteoblast-like MC3T3 cells. InsP₆, InsP_5, and InsP₄ dose-dependently (10–50 µmol/L) increased apoptosis as measured by acridine orange/ethidium bromide and caspase-3 staining. At these concentrations, InsP₆ was more potent than InsP₅ and InsP₄ in promoting apoptosis. To study the effects of endogenous higher InsPs on apoptosis, we used NaF and antimycin to change cellular levels of InsPs. NaF increases InsP₇ and InsP₈ levels by inhibiting InsP phosphatase, a process that is reversible by antimycin because InsP kinase is inhibited as a result of depletion of cellular ATP pools. Apoptosis was induced in MC3T3 cells in a NaF dose–dependent and time-dependent manner; 50% apoptosis was observed at 1 mmol/L NaF in 8 h. Prior treatment with 10 µmol/L antimycin for 30 min significantly reduced the NaF-induced apoptosis as compared with its control. The data indicated that NaF-induced apoptosis could be caused by an increase in InsP levels that was reversed by antimycin treatment. Additionally, we measured changes in lower InsP (InsP₁–InsP₄) levels during etoposide-induced apoptosis. Inositol tris- and tetrakisphosphate levels decreased dose dependently with a maximum decrease of 24% and 47%, respectively, at 50 µmol/L etoposide. Inositol mono- and bisphosphate levels either remained unchanged or increased marginally. The significance of these changes in InsP levels remains to be investigated. [Supported by Arkansas Space Grant Consortium grant to N. Ali.]

	Biomarkers

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Association of Hydroxynonenal- 1,N²-Propano-DNA-Adduct Levels in Human Lymphocytes with DNA Repair Gene XPA and Nutritional Markers in the Bavarian Nutrition Survey. Erwin Eder,¹ Odilia Popanda,² Paul Wanek,¹ Ellen Biskup,¹ and Jakob Linseisen.^{3 1}Department of Toxicology, University of Würzburg, Würzburg, Germany; ²Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany; ³Clinical Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

1,N²-Propanodeoxyguanosine adducts of 4-hydroxynonenal are appropriate biomarkers for cancer risk from lipid peroxidation. Adduct levels were measured in human lymphocytes in the Bavarian Nutrition Survey. The study investigated dietary behavior and lifestyle in a representative population sample in Bavaria: 1050 participants aged 13–80 y. In a substudy, 568 adult participants of both genders aged 18–80 y with complete dietary information were invited for blood sampling. Here we present the results of 278 samples evaluated to date. A significant inverse correlation of adduct levels was observed with eicosapentaenoic acid [20:5(n-3)] concentration in red blood cell membranes. No clear correlations were found between adduct levels and other fatty acids. Surprisingly, a positive correlation was seen between plasma vitamin C concentrations and adduct levels. No significant correlations were observed between adduct levels and plasma concentrations of other antioxidants. Socioeconomic status significantly correlated with adduct levels: the higher the status, the higher the adduct levels. The individual 1,N²-propanodeoxyguanosine adduct level can be modulated not only by lifestyle and nutrition factors but also by the individual DNA repair capacity. We also studied the influence of repair polymorphisms. With the XPD Asp³¹²Asn variants, no changes in adduct levels were seen. Adduct levels increased in the XPD Lys⁷⁵¹Gln variants from 54.3 mean adducts/10⁹ nucleotides in Lys/Lys (n = 126) to 60.6 in the Lys/Gln (n = 126) and to 63.2 in Gln/Gln (n = 40). In the XPA (–4G/A) variants, the adduct levels increased from 56.4 in variant G/G (n = 112) to 58.3 in G/A (n = 126) and to 64.4 in A/A (n = 40). After adjustment for nutrition factors, a significantly increased odds ratio of 2.5 (CI 1.05, 5.8) was determined for having high adduct levels in XPA A/A carriers, suggesting a higher cancer risk in these individuals.

DNA from Food as a Biomarker for Human Diet. Douglas Spangler,¹ Richard Rivlin,² and David S. Thaler.^{1 1}Raymond and Beverly Sackler Laboratory of Molecular Genetics and Informatics, New York, NY; ²Clinical Nutrition Research Unit, Strang Cancer Research Laboratory, Weill Medical College of Cornell University, New York, NY.

There is a recognized need to develop new, sensitive, quantitative, and objective biomarkers of human dietary intake (1). Species- and group (e.g., vegetable)-specific DNA sequences are potential biomarkers. We have developed a methodology of food-specific DNA analysis by Q(quantitative)PCR that can be applied to a wide range of clinical samples including blood, urine, saliva, and stool. Analyzing DNA in human biological fluids has the potential to provide novel biomarkers of dietary intake. Use of these biomarkers in clinical contexts will require and inform the understanding of individual variation in rates of digestion, intestinal transit, absorption, microbial processes, and excretion that are likely to be under genetic, physiological, and microecololgical controls. A clinical study is ongoing at the Rockefeller University Hospital. Our first analyses were consistent with the hypothesis that DNA sequences unique to vegetables and to fish were present in the blood of normal humans who ingest these foods. However, DNA from these blood samples was isolated with commercial kits and columns manufactured by Qiagen. Our subsequent sequencing of the PCR amplicons indicates that at least some of the "food DNA" signals derived from purification reagents, most likely the silica-containing spin columns. Others have reported finding related contaminants in commercial DNA purification reagents (2,3). Contamination of silica columns may be difficult to avoid because of the way they are currently manufactured. Taken together, we believe that these findings call into question the use of currently available commercial silica-based purification columns for certain contamination-sensitive DNA purifications for research, medical-diagnostic, and forensic applications. [Supported by NCI and by The Sloan Foundation.]

1. Johnson RK. Dietary intake—how do we measure what people are really eating? Obes Res. 2002;10: Suppl 1:63S–8S.[Medline]

2. van der Zee A, Peeters M, de Jong C, Verbakel H. Qiagen DNA extraction kits for sample preparation for Legionella PCR are not suitable for diagnostic purposes. J Clin Microbiol. 2002;40:1126–37.[Free Full Text]

3. Peters RP, Mohammadi T, Vandenbroucke-Grauls CM, Danner SA, van Agtmael MA, Savelkoul PH. Detection of bacterial DNA in blood samples from febrile patients: underestimated infection or emerging contamination? FEMS Immunol Med Microbiol. 2004;42:249–53.[Medline]

Dietary Carbohydrate as a Biomarker of Red Meat and Dairy Intake. Eric I. Park. Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.

High consumption of red meat has been associated with increased risk of colorectal cancer. However, the precise dietary component or the mechanism that accounts for this increased risk is unknown. One abundant component of red meat that is gaining interest is a type of carbohydrate moiety known as N-glycolylneuraminic acid (NGNA). NGNA accumulates on the cell surfaces of colon cancer, breast cancer, and hepatocellular carcinoma cells, whereas the surrounding normal cells have only trace amounts. Even more intriguing is how this accumulation occurs, because normal and cancerous human cells cannot synthesize NGNA. One likely source of NGNA is the consumption of red meat and dairy products, which are abundant in NGNA, and the subsequent metabolism of the NGNA by the same intracellular enzymes and transporters that metabolize endogenous sialic acids. Despite the possibility of NGNA serving as a biomarker of red meat and diary intake and for tagging and identifying cancer cells, little is known about the metabolism of dietary NGNA. Toward this goal, pilot studies were performed to determine the feasibility of using NGNA as a marker of red meat and dairy intake. First, a human cell line experiment showed that the amount of NGNA accumulation on the surface of cells depends on the NGNA concentration in the cell medium. Second, HPLC analyses showed that concentrations of NGNA were the same in raw and cooked meats. Third, the amounts of NGNA in human serum and urine samples were detected by HPLC and NMR methods, respectively. These studies suggest that the NGNA concentration in human samples may be useful as a marker of red meat and dairy consumption and a measurement to validate the real consumption levels of self-reported red meat and dairy intakes.

	Food Composition

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Sources of Flavonoids in the U.S. Diet Using USDA's Updated Database on the Flavonoid Content of Selected Foods. D.B. Haytowitz, S. Bhagwat, J.M. Holden, S.E. Gebhardt, and J. Harnly. USDA-ARS, Nutrient Data Laboratory and Food Composition Laboratory, Beltsville, MD.

Flavonoids are biologically active polyphenolic compounds widely distributed in plants and have been linked to various chemoprotective effects (1). USDA first released a database on the flavonoid content of foods in 2003. The database was recently updated using data from USDA analysis of 20 different flavonoid monomers from a nationwide sampling of 59 fruits, nuts, and vegetables, providing high-quality U.S. data not available in the earlier database. Data from 102 scientific papers were also added. The new database contains flavonoid data for 395 food items and is available on Nutrient Data Laboratory's (NDL's) Web site (2). These data were combined with data from NDL's Key Foods list derived from consumption data from the National Health and Nutrition Examination Survey to ascertain the intake of 5 classes of flavonoids—anthocyanidins, flavanones, flavonols, flavones, and flavan-3-ols—on a population basis. Black tea provided the largest amount of flavonols to the diet (32%), followed by onions (25%). Parsley was the largest contributor of flavones. Dried parsley contains a large amount—13.53 mg/100 g—though rarely is 100 g consumed at one time. Oranges (53%) and grapefruit juice (16%) provide significant amounts of the flavanones. Brewed tea provides the largest quantities of flavan-3-ols to the diet. Blueberries contributed the largest amount of anthocyanidins (31%), followed by bananas (21%) and strawberries (14%). Even though bananas contain considerably less anthocyanidins than any of the berries, U.S. consumption of bananas is much higher than that of individual berries. Daily per capita intake of flavonoids in the United States using these data were as follows: anthocyanidins, 5 mg; flavanones, 4 mg; flavones, 1 mg; flavonols, 10 mg; and flavan-3-ols, 112 mg. This expanded database provides researchers with new values on the flavononoid content of many more foods and should enable better assessment of the effect of flavonoid consumption on various chronic diseases.

4. Nichenametla SN, Taruscio TG, Barney DL, Exon JH. A review of the effects and mechanisms of polyphenolics in cancer. Crit Rev Food Sci Nutr. 2006;46:161–83.[Medline]

5. Nutrient Data Laboratory. Home page. 2006. Last Modified: 06/24/2006. Available from: http://www.ars.usda.gov/nutrientdata.

Nuts and Seeds as Sources of - and -Tocopherols. Robin G. Thomas and Susan E. Gebhardt. USDA-ARS Nutrient Data Laboratory, Beltsville, MD.

Some nuts and seeds are among the highest natural sources of vitamin E in the U.S. food supply. In its chief function as an antioxidant, vitamin E prevents free radical reactions, which is important in protecting cells from oxidative damage. Vitamin E has been associated with reduced risk of certain cancers such as colon, bladder, and prostate cancers. Recent studies have focused on effects of -tocopherol as well as -tocopherol. Of the 4 tocopherols (, ß, , and ), -tocopherol is the only one used to estimate the current Recommended Dietary Allowance (RDA) for vitamin E. The other tocopherols are absorbed and may have other functions but are not converted to -tocopherol in the body. The RDA for vitamin E is 15 mg/d of -tocopherol for adults. According to the National Health and Nutrition Examination Survey 2001–2002, >90% of adults do not meet the Estimated Average Requirement of 12 mg/d. Nuts and seeds are often cited as good sources of vitamin E. USDA recently updated tocopherol values in several nuts and seeds in the USDA National Nutrient Database for Standard Reference (SR). One-ounce portions of almonds, hazelnuts, and sunflower seeds provide >20% of the RDA for vitamin E, and Brazil nuts and pine nuts provide 10–20% of the RDA. One-ounce portions of cashews, macadamias, pecans, pistachios, black and English walnuts, flaxseed, and sesame seeds all provide 1–4% of the RDA. The highest nut and seed sources of -tocopherol are black walnuts and sesame seeds (28 mg/100 g), pecans (24 mg/100 g), pistachios (22 mg/100 g), and English walnuts and flaxseed (20 mg/100 g). These tocopherol values are derived from data from USDA studies, the food industry, and the scientific literature. Keeping SR up to date allows researchers to more accurately estimate nutrient intake, thus enabling them to study the relationships between diet and disease more effectively.

	Dietary Pattern and Cancer Risk

TOP Angiogenesis Apoptosis Biomarkers Food Composition Dietary Pattern and Cancer... Calorie Restriction Obesity Survivorship Colorectal Cancer Breast Cancer Prostate Cancer Herbs Soy Phytochemicals Lipids Vitamins Minerals

 
Diet and Cancer Prevention Knowledge, Beliefs, and Barriers among Students in Historically Black Colleges and Universities. Adelia C. Bovell-Benjamin, Peter N. Gichuhi, Chellani S. Hathorn, and Elaine Bromfield. Food and Nutritional Sciences, Tuskegee University, Tuskegee, AL.

In the United States, African Americans (AAs) have the highest cancer incidence and lowest survival rate. The reasons for this disparity have not been elucidated, but dietary factors, which are largely modifiable, have been implicated. Potentially adverse dietary practices implicated in cancer risk have been associated with AA diets. This study examined nutrition knowledge, dietary beliefs, and perceived barriers related to cancer that prevent AA college students from adopting eating behaviors consistent with National Cancer Institute (NCI) dietary guidelines. A cross-sectional, in-depth structured interview was administered to students attending two historically black colleges and universities. Four hundred fifty-six students (238 male; 216 female) aged 18–30 y participated. A little more than half of the students (56.4%) correctly identified the food lowest in fiber from a given list, and the majority (84.7%) knew that lower fat intake reduces cancer risk. Although 38% of the students believed that cancer may be related to what people eat, 34.6% did not believe that cancer was related to diet, and 35% did not know that consumption of salt-cured, salt-pickled, and smoked foods is associated with cancer. Most students (83%) were unaware of NCI dietary guidelines. However, 82% of the students indicated that nutrition counseling and specific instructions on how to make dietary changes to prevent cancer could help them to modify their eating behaviors. Students believed that fatty and fast foods increased cancer risk. Availability, food preferences, convenience, cost, lack of support from family members, and little knowledge of healthy foods and their preparation were identified as barriers to healthy eating.

Disparities in Environmental Risk Factors for Cancer Prevention in 2 Rural Cities. Chellani S. Hathorn, Peter N. Gichuhi, Elaine Bromfield, Samia Ibrahim, and Adelia C. Bovell-Benjamin. Department of Food and Nutritional Sciences, Tuskegee University, Tuskegee, AL.

The burden of cancer is unequally distributed among populations and geographic locations. Minority populations, especially low-income African Americans, have higher mortality rates from cancer than other ethnic groups. Environmental factors explain some of the disparity in cancers among low-income minority groups; therefore, assessment of environmental risk factors (such as diet and physical activity) in communities may be important in cancer-prevention efforts. This study compared the availability of healthy food and physical activity choices that encourage cancer risk reduction in 2 rural cities: 1 high income and 1 low income. An unobtrusive, observational cross-sectional study was conducted using the United States Department of Agriculture Thrifty Food Basket Checklist. Four convenience stores, 9 fast-food restaurants, 7 restaurants, 7 large supermarkets, and 3 mass merchandisers located within a 4-mile radius in both cities were inventoried. In the low-income city, none of the 3 large supermarkets carried low-sodium vegetables. The fast-food restaurant inventoried offered no fruit items in the low-income city, whereas 2 in the high-income city did. Low-fat milk was available in all the large supermarkets. Low-sodium, low-fat cheese was available in only 2 supermarkets in the low-income city and 5 supermarkets in the high-income city. Convenience stores and restaurants were the most common food outlets in the low-income city, and fast-food restaurants and supermarkets were most common in the high-income city. Of the 28 physical activity outlets inventoried, public recreational areas were common and mostly free in the high-income city but limited and had a fee in the low-income city. Community members in the low-income city had limited access to healthy food and physical activity choices.

Meat Consumption, N-Acetyl Transferase 1 and 2 Polymorphism, and Risk of Breast Cancer in Danish Postmenopausal Women. Rikke Egeberg,¹ Anja Olsen,¹ Herman Autrup,² Jane Christensen,¹ Connie Stripp,¹ Kim Overvad,³ and Anne Tjønneland.^{1 1}Institute of Cancer Epidemiology, The Danish Cancer Society, Copenhagen, Denmark; ²Department of Environmental and Occupational Medicine, Institute of Public Health, University of Aarhus, Denmark; ³Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.

In 1997 the World Cancer Research Fund concluded that meat intake might have a possible association with the risk of breast cancer. However, recent epidemiologic evidence concerning this relationship is controversial. We conducted a nested case-control study with 24,697 postmenopausal women included in the Diet, Cancer, and Health cohort study (1993–2000) to investigate the association between meat intake and breast cancer risk and whether polymorphisms in N-acetyltransferase 1 (NAT1) and 2 (NAT2) modified this association. A total of 378 breast cancer cases were identified and matched to 378 control subjects. The analyses were based on a conditional logistic regression analysis corresponding to a Cox proportional hazard model because of the study design used. All models were adjusted for baseline values of established risk factors for breast cancer. The incidence rate ratio (IRR) (95% CI) for breast cancer was 1.09 (1.02, 1.17) for total meat, 1.15 (1.01, 1.31) for red meat, and 1.23 (1.04, 1.45) for processed meat per 25 g/d increment in intake. The IRR (95% CI) in fast NAT1 acetylators compared with NAT1 slow acetylators was 1.43 (1.03, 1.99) and in intermediate to fast NAT2 acetylators compared with slow NAT2 acetylators was 1.13 (0.83, 1.54). Interaction analyses revealed that the positive associations between total meat intake and red meat intake and breast cancer risk were confined to intermediate –to fast NAT2 acetylators (P_interaction = 0.03 and 0.04), whereas no significant interaction was shown for NAT1 acetylator phenotypes. In conclusion, our findings support an association between meat consumption and breast cancer risk and a modifying effect of NAT2 polymorphism on the association.

Diet Quality Predicts BRCA-Associated Breast Cancer Risk. André Nkondjock and Parviz Ghadirian. Epidemiology Research Unit, RC, CHUM, Montreal, Canada.

Although it has been suggested that dietary energy intake restriction may be related to reduced BRCA-associated breast cancer risk, it is currently not known whether overall diet quality could predict the risk among women with deleterious mutations in BRCA1 and BRCA2 genes who already have an elevated breast cancer risk. To assess possible relationships between diet quality—reflected by the Alternate Healthy Eating Index (AHEI), the Diet Quality Index-Revised (DQI-R), the alternate Mediterranean Diet Index (aMED), and the Canadian Healthy Eating Index (CHEI)—and BRCA-associated breast cancer risk, a case-control study was carried out within a cohort of 80 French-Canadian families involving 89 carriers of BRCA genes affected by breast cancer, 48 nonaffected carriers, and 46 nonaffected noncarriers. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in unconditional logistic regression models. After adjustment for age, physical activity, and total energy intake, we did not detect any association between AHEI or aMED and breast cancer. However, a strong and significant inverse relationship was apparent between DQI-R and CHEI and BRCA-associated breast cancer risk. ORs comparing the highest and lowest tertiles of diet quality scores were 0.35 (95%CI 0.12 to 1.02; P_trend = 0.034) for DQI-R and 0.18 (95%CI 0.05 to 0.68; P_trend = 0.006) for CHEI, respectively. These inverse associations were not the result of a link with any specific component of the diet quality indexes. Findings from this study suggest that dietary guidelines reflected by DQI-R and CHEI may constitute preventive strategies for reducing BRCA-associated breast cancer risk.

The PRECISE Pilot Trial: Investigating the Relation among Selenium, Homocysteine, and Folate in an Elderly UK Population. Bram Bekaert,¹ Matthew Lewis Cooper,¹ Fiona Green,¹ John Scott Jr,² and Margaret P. Rayman.^{1 1}School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UK; ²School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

Colorectal cancer risk is associated with folate status (1), whereas selenium was shown to modify the risk of several cancers (2). Both play an important role in 1-carbon metabolism that involves the remethylation of homocysteine to methionine, which in turn is an important modifier of DNA methylation in neoplasia (3). We investigated the interaction among the 3 dietary factors in 501 healthy UK volunteers aged 60–74 y to determine the effect of selenium (Se) supplementation on folate and homocysteine (tHcy) concentrations. Volunteers were randomly assigned to receive placebo or 100, 200, or 300 µg/d of Se-enriched yeast for 6 mo in a double-blind, placebo-controlled trial. There was no significant effect of Se supplementation on the change in tHcy in any treatment groups in accordance with the findings of Venn et al. (4). At 6 mo, folate levels remained inversely correlated with tHcy in all treatment groups. Baseline folate concentration was significantly different between men and women (11.44 vs. 13.35 nmol/L, respectively, P = 0.013), and men had higher tHcy concentrations than women (mean ± SD, 11.59 ± 4.75 vs. 10.56 ± 4.68 µmol/L, P = 0.0002). Baseline plasma tHcy correlated inversely with both plasma folate and plasma Se in men, with folate accounting for 2.6% and Se for 1.8% of the variance. The inverse correlation of baseline Se and homocysteine in this elderly population agrees with results of other human studies (4–6), although the magnitude of the effect explained by Se when folate is taken into account was much lower and was seen only in men. Protein intake was inversely correlated with tHcy (7) and could explain the inverse relation between Se and tHcy at baseline. Dietary protein intake of the population will be investigated because high-protein foods such as meat and poultry are the major sources of Se in the UK. [Research supported by Cancer Research UK.]

6. Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, Winkvist A, Palmqvist R. Low folate levels may protect against colorectal cancer. Gut. 2006;55:1461–6.[Abstract/Free Full Text]

7. Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276:1957–63.[Abstract]

8. Uthus EO, Ross SA, Davis CD. Differential effects of dietary selenium (Se) and folate on methyl metabolism in liver and colon of rats. Biol Trace Elem Res 2006;109:201–14.[Medline]

9. Venn BJ, Grant AM, Thomson CD, Green TJ. Selenium supplements do not increase plasma total homocysteine concentrations in men and women. J Nutr. 2003;133:418–20.[Abstract/Free Full Text]

10. Gonzalez S, Huerta JM, Alvarez-Uria J, Fernandez S, Patterson AM, Lasheras C. Serum selenium is associated with plasma homocysteine concentrations in elderly humans. J Nutr. 2004;134:1736–40.[Abstract/Free Full Text]

11. Klapcinska B, Poprzecki S, Danch A, Sobczak A, Kempa K. Selenium levels in blood of upper Silesian population: evidence of suboptimal selenium status in a significant percentage of the population. Biol Trace Elem Res. 2005;108:1–15.[Medline]

12. Stolzenberg-Solomon RZ, Miller ER 3rd, Maguire MG, Selhub J, Appel LJ. Association of dietary protein intake and coffee consumption with serunm homocysteine concentrations in an older population. Am J Clin Nutr. 1999;69:467–75.[Abstract/Free Full Text]

	Calorie Restriction

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Glucose Restriction Prevents Epigenetic Changes Associated with Carcinogenesis. Joel B. Berletch, Liang Liu, Lucy G. Andrews, and Trygve O. Tollefsbol. Department of Biology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL.

It is well documented that calorie restriction (CR) is an effective experimental means for decreasing cancer risk in various model organisms. It is unlikely, however, that most humans would be willing to maintain a 30–50% reduction in calorie intake for the bulk of their adult life span, even if it means reduced cancer risk. A better option is to identify critical CR mimetics, agents that can induce the same beneficial effects as CR but without dieting, that can be used in dietary intervention. Dietary glucose may be the key factor determining the beneficial effects of CR in reducing the risk of cancer because reduced glucose metabolism is thought to have health- and longevity-promoting effects without actually decreasing food intake in rats. In fact, our preliminary studies indicated for the first time that glucose-restricted human fibroblasts undergo senescence at a slower rate than cells receiving normal levels of glucose. Early studies indicated that CR can change the level of gene products that are involved in epigenetic modifications of important cellular processes such as acetylation of histone proteins. DNA methylation is another important epigenetic process that plays a critical role in gene regulation. Genome-wide hypomethylation occurs in aging cells and is associated with cancer. We have found that the induction of the DNA methyltransferase 1 gene, which is associated with cancer, is markedly decreased in glucose-restricted MCF-7 breast cancer cells. Taken together, these studies indicate that dietary glucose restriction may have important cancer-preventive implications.

The Effect of Intermittent Versus Chronic Energy Restriction on Breast Cancer Risk Biomarkers in Premenopausal Women: A Randomized Pilot Trial. Michelle Harvie,¹ Mary Chapman,¹ Jack Cuzick,² Alan Flyvbjerg,³ Penny Hopwood,⁴ Susan Jebb,⁵ Gaenor Parfitt,⁶ and Anthony Howell.^{4 1}School of Medicine, Withington Hospital, The University of Manchester, Manchester, UK; ²CRUK Department of Epidemiology and Statistics, Wolfson Institute, London, UK; ³Medical Research Laboratories, Aarhus University, Denmark; ⁴CRUK Department of Medical Oncology, Christie Hospital, Manchester, UK; ⁵MRC Human Nutrition Research Group, Cambridge, UK; ⁶Scholl School of Sport and Health Science, University of Exeter, UK.

Postmenopausal breast cancer risk increases 2-fold in women who gain significant amounts of weight (1), and there is evidence that energy restriction may reduce risk (2). Animal studies indicate that intermittent energy restriction (IER) reduces risk and may be superior to continuous energy restriction (CER) (3). We showed that chronic energy restriction reduces biomarkers of breast cancer in women at risk but is hard to maintain. We hypothesize that IER may be superior to CER in reducing biomarkers of breast cancer risk and may also be more acceptable to women. We are undertaking a 6-mo randomized trial to compare the 2 approaches in 104 premenopausal women aged 30–45 y, at high risk for breast cancer because of family history and adult weight gain of >7 kg. Women will be randomly assigned to either CER (75% estimated energy requirements: 1500 kcal 7 d/wk) or IER (75% estimated energy requirements: 650 kcal for 2 d and 1800 kcal 5 d/wk) over 6 mo. Study endpoints will be measures of insulin sensitivity (homeostasis model assessment, sex hormone binding globulin, testosterone), potential breast cancer growth factors (insulin-like growth factor axis, leptin, adiponectin), inflammatory markers (C-reactive protein, sialic acid), oxidative stress marker (urinary F2 isoprostane), weight and body composition (waist-hip circumference, fat-free and total fat mass). The relative acceptability of IER and CER will be assessed using quality of life questionnaire (RAND SF-36) and scales of behavior change and adherence. The relative efficacy and acceptance of IER and CER will inform future weight loss programs to prevent breast cancer. Currently 14 women have been recruited to the study (5 CER and 9 IER). This pilot study will be completed by December 2007.

13. Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC. Dual effects of weight and weight gain on breast cancer risk. JAMA. 1997;278:1407–11.[Abstract]

14. Harvie M, Howell A, Vierkant RA, Kumar N, Cerhan JR, Kelemen LE, Folsom AR, Sellers TA. Association of gain and loss of weight before and after menopause with risk of postmenopausal breast cancer in the Iowa women's health study. Cancer Epidemiol Biomarkers Prev. 2005;14:656–61.[Abstract/Free Full Text]

15. Cleary MP, Jacobson MK, Phillips FC, Getzin SC, Grande JP, Maihle NJ. Weight-cycling decreases incidence and increases latency of mammary tumors to a greater extent than does chronic caloric restriction in mouse mammary tumor virus- transforming growth factor- female mice. Cancer Epidemiol Biomarkers Prev. 2002;11:836–43.[Abstract/Free Full Text]

	Obesity

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Dietary Fat Predicts Biochemical Failure Only among Prostate Cancer Patients with Lower Gleason Scores. Yuko Yamamura,¹ Patricia Troncoso,² and Sara S. Strom.¹ Departments of ¹Epidemiology and ²Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.

We demonstrated that obesity at diagnosis (BMI > 30) is a predictor of biochemical failure, measured by rising prostate-specific antigen, in prostate cancer (PCa) patients treated with radical prostatectomy. Given that Gleason score is the best predictor of biochemical failure, we compared patients with less aggressive PCa [LAPCa; Gleason score < 7(3+4)] vs. more aggressive PCa [MAPCa; Gleason score > 7(4+3)] with respect to factors associated with obesity, such as dietary fat intake and weight gain, along with clinicopathologic and demographic variables. We hypothesize that risk of biochemical failure in LAPCa versus MAPCa is modulated by different factors. In a well-characterized cohort of 390 Caucasian men with PCa treated initially with only radical prostatectomy, we used multivariable Cox proportional hazards models to estimate risk of progression. As expected, in both groups pathologic stage and surgical margin involvement remained independent predictors of biochemical failure. Of 213 patients with LAPCa, energy-adjusted high-fat intake [hazard ratio (HR) = 3.59, P = 0.04] was a significant independent predictor of biochemical failure; however, no association was found with weight change. In MAPCa patients, annual weight change between age 25 and diagnosis (continuous) but not dietary fat intake was associated with increased risk of biochemical failure (HR = 1.82, P = 0.03). These data suggest that different combinations of clinicopathological and environmental factors, such as diet and weight gain, play different roles in LAPCa versus MAPCa in predicting biochemical failure after radical prostatectomy. To further our understanding of these findings, we plan to identify and explore possible mechanisms underlying our results. [Supported by NCI CA84964, CA90270, NIEHS ES07784.]

	Survivorship

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The Effect of a Lifestyle Intervention on Body Weight, Psychological Health Status, and Risk Factors Associated with Disease Recurrence in Women Recovering from Breast Cancer Treatment: Study Protocol and Interim Findings. Emma Scott,¹ Amanda Daley,¹ Nicola Woodroofe,² Robert Coleman,³ Hilary Powers,⁴ Nanette Mutrie,¹ Vanessa Siddall,¹ Helen Crank,¹ and John M. Saxton.^{1 1}Centre for Sport and Exercise Science, ²Division of Genomic Medicine, ³Cancer Research Centre, and ⁴Human Nutrition Unit, Sheffield Hallam University, Sheffield, UK.

A large proportion of women gain weight after breast cancer diagnosis, and there is evidence that heavier women have an increased risk of disease recurrence and death compared with normal-weight women. After diagnosis, women can also experience high levels of emotional distress, which might affect stress hormone levels and impair immune function, thereby affecting cancer outcome. The aims of this research are to investigate the effects of a lifestyle intervention on body weight and psychological well-being in postmenopausal women recovering from breast cancer treatment and to determine the relation between the changes in these variables and circulating biomarkers associated with disease recurrence and survival. Patients are randomly assigned to 2 groups: a 6-mo lifestyle intervention or a normal-care control group. The lifestyle intervention combines dietary energy restriction and nutrition education with supervised aerobic exercise training. It was hypothesized that the lifestyle intervention would evoke a reduction in body weight and an improvement in psychological well-being. Furthermore, a decrease in body weight is expected to be associated with reductions in the circulating levels of estrogens and inflammatory mediators. Associations among changes in psychological well-being, stress hormone levels, and immune function are also being studied. Body weight and body composition, anthropometric measures, and psychological well-being are assessed at the start, midpoint, and end of the study, whereas circulating biomarkers are measured pre- and postintervention. Preliminary 12-wk findings for 8 women show greater reductions in body weight for the intervention versus control group (–1.58 ± 3.00 kg vs. –0.83 ± 2.11 kg, mean ± SD, respectively). Compliance to the intervention has been excellent, with women attending at least 87.5% of the dietary counseling and exercise sessions.

Strategies for Health: Follow-Up Care Practices and Beliefs among African American Breast Cancer Survivors. Renee Royak-Schaler,¹ Susan Racine Passmore,¹ Katherine Tkaczuk,¹ Joseph Finkelstein,¹ Jimmie Drummond,¹ Peggy D. Nicholson,² Alva P. Hutchison,³ and Shahinaz M. Gadalla.^{1 1}University of Maryland School of Medicine, Baltimore, MD; ²Sisters Network Baltimore Chapter, Baltimore, MD; ³American Cancer Society, South Atlantic Division Inc., Atlanta, GA.

There is a gap in scientific understanding regarding the psychosocial and health concerns and follow-up care practices of African American breast cancer survivors after primary treatment is complete. Evidence-based guidelines for survivorship care are not readily available to clinicians (1). To address this gap we investigated 1) patient perceptions of patient-physician communication and follow-up care practices and 2) strategies for developing follow-up care plans that address the special needs of African American breast cancer survivors. Four focus groups were conducted with 39 African American women, mean age 55 y, to investigate the following themes: patient-physician communication and decisionmaking about follow-up care; other sources of information used in developing follow-up care plans (e.g., Internet or print material); and preferences and avenues for information delivery to survivors. Group members also completed survey questionnaires designed to support the focus group discussions. Participants identified no clear plan valued over others as a means to reduce their risk of breast cancer recurrence. They reported receiving minimal information from their physicians about state-of-the-art strategies for reducing their risk of recurrence, for example, weight management by low-fat diet and physical activity. Although 87% said they were satisfied with the information received from medical professionals, they acknowledged that it did not specifically target the health concerns of African American women (e.g., healthy eating in the context of traditional high-fat diets). African American survivors had a critical need for guidance from healthcare professionals in developing feasible plans of self-care that target the context of their lifestyles for improving breast cancer outcomes. [Supported by grants from the Lance Armstrong Foundation and the Susan G. Komen Breast Cancer Foundation, Maryland Affiliate.]

16. Institute of Medicine. From cancer patient to cancer survivor, lost in transition. Washington, DC: National Academies Press; 2006.

	Colorectal Cancer

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Novel Combinations of Chemopreventive Agents Demonstrate a Synergistic Effect against Cell Proliferation in Colon Cancer Cell Lines. Naveen Kanthamneni and Sunil Prabhu. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA.

We studied synergistic chemopreventive effects of a dual combination of agents (aspirin with folic acid; aspirin with calcium) against cell proliferation in colon cancer cell lines, SW-480 and HT-29. These cells were grown according to previously established protocols. On reaching 75–80% confluence, 5 x 10³ cells were transferred into each well of a 96-well microplate to which different concentrations of drug alone (aspirin, folic acid, or calcium) or its dual combinations (aspirin with folic acid or aspirin with calcium) were added. The plates were then incubated for 24–48 h. Using an XTT assay method, we measured cell viability with a microplate reader at wavelength 450 nm. With the SW-480 cell line, the combination of aspirin (5 mmol/L) with folic acid (0.5 mmol/L) demonstrated a 22% decrease in cell viability when compared with the individual drugs at the same concentrations after 24 h. With the HT-29 cell line, a similar phenomenon was observed with a 20% decrease in cell viability at low concentrations of aspirin (5 mmol/L) and folic acid (0.5 mmol/L). With aspirin and calcium combinations tested on SW-480, no synergistic effects on cell viability during the first 24 h of incubation were observed. However, after 48 h a dose-dependent relationship was apparent as progressively increasing amounts of aspirin (5, 10, and 15 mol/L) demonstrated a 28–62% decrease in cell viability, respectively, when mixed with calcium (15 mmol/L). Aspirin, folic acid, and calcium are currently being investigated individually as chemopreventive agents in the fight against colon cancer. Combining these agents and demonstrating significant synergism provide promising data for developing future chemopreventive strategies in colon cancer. These results will also be useful for investigating combined chemoprevention of colon cancer using a nanotechnology-based therapeutic system.

Combination of Fish Oil and Pectin Suppressed ß-Catenin Nuclear Translocation, an Important Molecular Event in Colon Carcinogenesis. J. Vanamala,¹ A. Glagolenko,² R.J. Carroll,³ M.E. Murphy,⁴ S.S. Taddeo,¹ R.S. Chapkin,¹ N.D. Turner,¹ and J.R. Lupton.^{1 1}Faculty of Nutrition, ²Department of Nuclear Engineering, and ³Department of Statistics, Texas A&M University, College Station, TX.

We previously showed that a fish oil and pectin diet enhances spontaneous colonocyte apoptosis when compared with a corn oil and cellulose diet. We also demonstrated that the fish oil and pectin diet suppresses prostaglandin E synthase-2 (prostaglandin pathway), ß-catenin (Wnt pathway), and peroxisome proliferator-activated receptor ß/ (nuclear receptor) levels in rats exposed to radiation and chemical carcinogen. We hypothesized that a diet containing fish oil and pectin may also suppress ß-catenin nuclear translocation. To test this hypothesis, 40 rats were provided diets containing either fish oil and pectin or corn oil and cellulose. Rats were exposed to either 0 or 1 Gy, 1 GeV/nucleon Fe-ion irradiation 3 wk after starting the diets. All rats were injected with azoxymethane (15 mg/kg body wt), a colon-specific carcinogen, 10 and 17 d after irradiation. Thirty-one weeks after the last azoxymethane injection, rats were killed, and the proportion of cells with nuclear ß-catenin staining was determined within 26 crypt columns/rat by immunohistochemistry. The fish oil–pectin diet suppressed (P 0.01) nuclear translocation of ß-catenin compared with the corn oil–cellulose diet. However, irradiation did not influence the nuclear translocation of ß-catenin. These data suggest that enhanced apoptosis observed in rats consuming a fish oil–pectin diet could be attributed to both the suppressed levels of ß-catenin in the colonocytes and the attenuated nuclear translocation. Thus, this study provides evidence that the mechanism of action by which the fish oil and pectin diet induces apoptosis involves the prostaglandin and Wnt signaling pathways. [Funded by AICR 05B094, NIH CA61750, CA82907, NSBRI NASA NCC 9–58, CA59034, and NIEHS P30-ES09106.]

Dietary Flax Products Suppress the Formation of Azoxymethane-Induced Colon Cancer in Fisher 344 Male Rats. Darlene S. Williams,¹ Martha Verghese,¹ Judith Boateng,¹ Lloyd T. Walker,¹ Louis Shackelford,¹ Janak Khatiwada,¹ David Asiamah,¹ and Chandramohan B. Chawan.^{2 1}Nutrition and Carcinogenesis Laboratory, Department of Food and Animal Sciences, Alabama A&M University, Normal, AL; ²USDA/AMS/PY, Washington, DC.

Flax is a rich source of bioactive components such as PUFA (fat); dietary fiber; -linolenic acid (ALA), the essential (n-3) fatty acid; and lignans, which are phytoestrogens and antioxidants. This study was designed to determine the anticarcinogenic effect of flaxseed meal (FSM; 10% and 20%) and flaxseed oil (FSO; 7% and 14%) on azoxymethane (AOM)-induced colon cancer in Fisher 344 male rats at the initiation (I), promotion (P), and initiation plus promotion (I + P) stages of carcinogenesis. After an acclimatization period of 1 wk, 14 groups of Fisher 344 male weanling rats (15 per group) were created; 2 control groups were fed AIN 93G diet and AIN 93G + 14% soybean oil. The remaining 12 groups were assigned to 10% and 20% FSM (I, P, and I+P) and 7% and 14% FSO (I, P, and I+P). All rats received 16 mg/kg body weight of AOM at ages 7 and 8 wk. At age 45 wk rats were killed by CO₂ asphyxiation. Tumor incidence and size, respectively, were significantly (P < 0.05) lower in groups fed FSM (10% and 20%) and FSO (7% and 14%) compared with controls. The ratio of tumors to tumor-bearing rats for groups fed the control diet, 10% FSM, and 20% FSM (I, P, and I+P) were 3.80; 1.60, 1.10, 1.0; and 1.66, 1.1, 1.0, respectively. In rats fed the 7% FSO, and 14% FSO (I, P, and I+P), the ratios were 1.40, 1.25, 1.42 and 1.90, 1.40, 1.42, respectively. The activity of glutathione-S-transferase (a phase II detoxification enzyme) was significantly (P < 0.05) higher in rats fed 10% and 20% FSM and 7% and 14% FSO compared with controls. The results of this study indicated that dietary flaxseed products may suppress colon tumors, particularly at the promotion stage, and may therefore be a potential chemopreventive agent.

Antitumor and Cytotoxic Properties of Red Kidney Beans (Phaseolus vulgaris): An In Vitro and In Vivo Model. Judith Boateng,¹ Martha Verghese,¹ Lloyd T. Walker,¹ Louis Shackelford,¹ Janak Khatiwada,¹ Chandramohan B. Chawan,² Darlene S. Williams,¹ and David Asiamah.^{1 1}Nutrition and Carcinogenesis Laboratory, Department of Food and Animal Sciences, Alabama A&M University, Normal, AL; ²USDA/AMS/PY, Washington, DC.

Dry beans are a good source of fiber and phytochemicals such as flavonoids and phenolic compounds and may be responsible for preventing the onset of chronic diseases. We examined the antitumor effects of red kidney beans (RKB) on azoxymethane (AOM)-induced colon tumors [aberrant crypt foci (ACF) and endpoint tumor model (EPTM)] and the cytotoxic effects of aqueous RKB extracts on colon cancer cell line CaCo2. For the ACF study, 12 Fisher 344 male rats were fed AIN-93G control diet (C; n = 6) and 20% RKB (n = 6) for 13 wk. For EPTM, 2 groups of rats (n = 14) were fed C and 20% RKB. All rats received 2 s/c injections of AOM at ages 7 and 8 wk (16 mg/kg body weight in saline). At 17 wk (ACF) and 45 wk of age (EPTM), rats were killed by CO₂ asphyxiation. For the lactate dehydrogenase assay, cells were maintained in Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum. Cells were seeded and incubated at 37°C, 7% CO₂, until a monolayer developed. Cells were incubated (24 and 48 h) with selected concentrations (0.5–25 mol/L) of RKB extract. The total number of ACF was 183 and 51 for C and 20% RKB, respectively. Activity of glutathione-S-transferase, a phase II detoxifying enzyme, was 20.38 and 48.84 in rats fed C and 20% RKB, respectively. Tumor size per rat (mm) and tumors per tumor-bearing rat for C and 20% RKB were 13.13 and 1.16, and 3.39 and 0.78, respectively. Lactate dehydrogenase activity in CaCo2 cells after 24 and 48 h incubation with RKB extracts ranged from 13.8% to 62.8% and 23.5% to 84.1%, respectively. RKB significantly (P < 0.05) reduced the incidence of chemically induced colon tumors, and RKB extracts exhibited cytotoxic effects on colon cancer cell lines and thus may play a significant role in chemoprevention.

	Breast Cancer

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In Utero and Prepubertal Exposures to Indole-3-Carbinol Have Opposing Effects on Mammary Tumorigenesis in Rats. Leena Hilakivi-Clarke,¹ Bin Yu,¹ Moira B. Hilsher,¹ and William Helferich.^{1,2 1}LCCC, Department of Oncology, Georgetown University, Washington, DC; and ²Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL.

The age when an individual is exposed to various hormones or dietary compounds has a profound effect on how these compounds alter susceptibility to developing breast cancer. We used an animal model to investigate whether a maternal dietary exposure during pregnancy or prepubertally during postnatal weeks 2 and 3 to indole-3-carbinol (I3C), present in cruciferous vegetables, affects DMBA-induced mammary tumorigenesis in rats. The dose of I3C used, 2000 ppm, was previously used in several cancer prevention studies. Results indicated that offspring of dams fed I3C during pregnancy developed more mammary tumors than control rats fed AIN93 diet (increase in mammary tumor incidence P < 0.06, tumor multiplicity P < 0.01), whereas prepubertal exposure was highly protective (reduction in incidence P < 0.001). Changes were also seen in circulating estradiol (but not progesterone) concentrations and mammary gland morphology, but these changes were not consistent with the observed differences in mammary tumorigenesis. Furthermore, as previously reported in animals exposed to I3C in adulthood, levels of estrogen receptor and aryl hydrocarbon receptor were reduced, and apoptosis was increased in the mammary glands of the rats exposed to I3C early in life; however, these changes were not consistent with the changes in mammary tumorigenesis. Maternal exposure to I3C significantly down-regulated tumor suppressor gene APC (P < 0.03) and, in agreement with this result, increased nuclear localization of ß-catenin (P < 0.04) and TCF4 expression (P < 0.05) in the offspring's mammary gland, suggesting that activation of the Wnt signaling pathway in the I3C offspring may explain why in utero exposure increased later susceptibility to developing mammary tumors. We are now investigating whether prepubertal I3C exposure down-regulated the Wnt pathway.

Phytoestrogens and Breast Cancer Progression: A Prospective Study. Louiza Velentzis, Ann Titcomb, Anna McConnochie, Annie Perkins, Paula Stavrinos, Patricia Leathem, and Tony Leathem. Department of Surgery, University College, London, UK.

Phytoestrogens are chemicals commonly found in foods of plant origin, and they can mimic the female sex hormone estrogen. The effects can be dramatic, such as the infertility in sheep from eating clover plants. Breast cancers are generally driven by estrogen, and effective treatments are based on removing or blocking this hormone. Can phytoestrogens in the diet or in dietary supplements act like estrogen and stimulate breast cancer growth, or can they block estrogen receptors like treatment with tamoxifen and slow down cancer growth? We are studying phytoestrogen levels in women with breast cancer to help answer this. In our study design, 2000 women in the United Kingdom with invasive breast cancer are recruited at diagnosis at 40 regional cancer centers, and their diet, phytoestrogen excretion, and clinical progress are monitored annually for 5 y. The aim is to seek any association between phytoestrogen intake and time to death or time to first recurrence. Urine is collected to measure 9 phytoestrogens, and blood is collected to measure biomarkers and polymorphisms. Each year patients complete dietary questionnaires—the food frequency and 7-d food diary questionnaires developed for the European Prospective Investigation into Cancer and Nutrition—plus lifestyle, quality-of-life, and complementary therapies questionnaires. Phytoestrogen intake is measured from 24-h and random urine samples with mass spectrometry and an immune assay. The phytoestrogens currently measured are enterodiol, enterolactone, secoisolariciresinol, equol, daidzein, genistein, naringenin, glycitein, and O-desmethylangolensin. We have recruited 950 patients so far.

Alcohol Drinking, Acetaldehyde Accumulation, and Oxidative Stress Promotion in Mammary Tissue: Their Potential Role in Ethanol-Induced Breast Cancer. Gerardo D. Castro, Aurora M.A. Delgado de Layño, Silvia L. Fanelli, Maria E. Maciel, Maria I. Díaz Gómez, and Jose A. Castro. Centro de Investigaciones Toxicológicas, CITEFA-CONICET, Buenos Aires, Argentina.

Previous studies from our laboratory reported the presence of several pathways of metabolic activation of ethanol to acetaldehyde and hydroxyl free radicals as well as the promotion of oxidative stress. In the present studies, we tested the possibility that after alcohol drinking, acetaldehyde accumulates in mammary tissue to reach concentrations higher than in blood. Three different doses of alcohol (low, medium, and high) were tested, and acetaldehyde concentrations in breast, liver, and blood were measured at times ranging from 1 to 24 h. We also measured alcohol dehydrogenase, aldehyde dehydrogenase, and CYP2E1-mediated p-nitrophenol hydroxylase activities. Oxidative stress induced hydroperoxide formation as determined with the xylenol orange procedure; -tocopherol and glutathione content determinations are in course for each dose at different times of exposure. Hydroperoxide levels were increased at 6 h for the highest dose tested. Acetaldehyde concentrations at the 3 alcohol doses tested were always higher than those in blood. Peak concentrations of acetaldehyde in liver, although higher than those in breast, appeared to decrease to blood levels following a similar time sequence. Limited activities of alcohol dehydrogenase and aldehyde dehydrogenase in mammary tissue were observed. The microsomal CYP2E1-mediated p-nitrophenol hydroxylase in mammary tissue was several times smaller than that in liver. In summary, results suggest that the mutagen acetaldehyde, either formed in situ or in small amounts continuously arriving via blood, tends to accumulate in mammary tissue as a consequence of a limited capacity of mammary tissue for detoxification. [Supported by grants from ANPCyT-SECyT (PICT 05–6045) and from UNSAM (PIB S05/03), Argentina.]

	Prostate Cancer

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Toxic Effects of Ethanol Administration on Rat Prostate and the Controversies about the Role of Alcohol Drinking in Prostate Cancer Induction. Maria I. Díaz Gómez, Carmen Rodríguez de Castro, Silvia L. Fanelli, Aurora M.A. Delgado de Layño, Martin H. Costantini, Jose A. Castro, and Gerardo D. Castro. Centro de Investigaciones Toxicológicas, CITEFA-CONICET, Buenos Aires, Argentina.

The potential correlation between alcohol consumption and prostate cancer led to controversial findings. To shed some light on the problem, it is critical to learn whether interaction with ethanol leads to alterations in prostate tissue similar to those attributed to alcohol-promoted liver cell injury or cancer. To that end, previous studies from our laboratory showed that cytosolic and microsomal fractions from the rat ventral prostate are able to biotransform ethanol to acetaldehyde and 1-hydroxyethyl free radicals. Present biochemical and ultrastructural studies were performed in Sprague Dawley male rats fed with a nutritionally adequate liquid diet (1) containing ethanol for 28 d and compared with adequately pair-fed controls. Prostate microsomal fractions were found to exhibit a CYP2E1-mediated p-nitrophenol hydroxylase metabolism, and that activity was induced by repetitive ethanol drinking. Cytosolic activation of acetaldehyde led to acetyl radical, as detected by spin trapping with PBN and GC-MS analysis. Low activities of alcohol dehydrogenase and aldehyde dehydrogenase were observed in prostate tissue, and acetaldehyde accumulation occurred after ethanol administration. An increased oxidizability of prostatic lipids was detected by the t-butylhydroperoxide–promoted chemiluminescence emission test and by the increased levels of lipid hydroperoxides (shown by the xylenol orange method). Ultrastructural alterations in the epithelial cells were observed. They consisted of marked condensation of chromatin around the perinuclear membrane, moderate dilatation of their endoplasmic reticulum, and some epithelial cells undergoing apoptosis. In summary, alcohol drinking leads to the formation of mutagenic acetaldehyde and to tumor-promoting oxidative stress. However, it exerts direct and indirect proapoptotic effects in the prostate epithelial cells. The balance between these 2 actions might explain, at least in part, many controversial results observed in epidemiologic studies. [Supported by grants from CONICET (PIP 02323) and the University of San Martín (PIDA UF013), Argentina.]

17. Lieber CS, De Carli LM. Liquid diet technique of ethanol administration: 1989 update. Alcohol Alcohol. 1989;24:197–211.[Abstract/Free Full Text]

Insulin-like Growth Factor-I Stimulates Lipid Metabolism in Prostate Cancer Cells. Shihua Wang,¹ Lei Shen,² Valerie L. DeGroff,¹ and Steven K. Clinton.^{1 1}Division of Hematology and Oncology, Department of Internal Medicine, and ²Division of Epidemiology and Biometrics, The Ohio State University College of Medicine and Public Health, Columbus, OH.

The hormone and growth factor insulin-like growth factor-I (IGF-I) has emerged as a potential promoter of prostate carcinogenesis. IGF-I exhibits pleiotropic activities including the stimulation of prostate tumor cell proliferation, survival, and resistance to apoptosis. To better understand how IGF-I modulates these processes and to identify novel biomarkers for future rodent and human studies, we examined global gene expression profiles (Affymetrix GeneChip - Rat Genome U34A) in AT6.3 rat prostate cancer cells after treatment for 24 h in serum-free medium (SFM), SFM with 10% fetal bovine serum, or SFM with 50 µg/L IGF-I (n = 6 each). The microarray data were analyzed by dChip and SAM software. Lipids are important structural components for cells and serve as signaling mediators associated with many critical cellular functions. This study reports our findings regarding IGF-I–regulated pathways involving lipid metabolism. Our results showed that the majority of genes involved in de novo cholesterol synthesis from mevalonate were significantly up-regulated by IGF-I and frequently down-regulated by serum. These genes included HMG-CoA synthase 1 (q = 1.2), HMG CoA reductase (q = 1.1), mevalonate kinase (q = 0), farnesyl-PP synthase (q = 0), farnesyl diphosphate farnesyl transferase 1 (q = 0.4), squalene epoxidase (q = 0), and 7-dehydrocholesterol reductase (q = 0). In addition, several enzymes related to fatty acid metabolism, such as acyl-CoA synthetase 3 (q = 0.9), and stearoyl CoA desaturase 1 (q = 0), were also up-regulated by IGF-I. These microarray observations were validated by subsequent RT-PCR and Western blots. Mevinolin (lovastatin), an inhibitor of HMG-CoA reductase, inhibited IGF-I–stimulated AT6.3 cell proliferation