cancer-preventions

Cancer Prevention Research 2, 850, October 1, 2009.doi: 10.1158/1940-6207.CAPR-08-0238

A Model of Gene-Environment Interaction Reveals Altered Mammary Gland Gene Expression and Increased Tumor Growth following Social Isolation

J. Bradley Williams1, Diana Pang1, Bertha Delgado2,3, Masha Kocherginsky4, Maria Tretiakova2, Thomas Krausz2, Deng Pan1, Jane He1, Martha K. McClintock3 and Suzanne D. Conzen1,3,5

Authors’ Affiliations: Departments of 1 Medicine and 2 Pathology, 3 The Institute of Mind and Biology, 4 Department of Health Studies, and 5 Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois

Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression—both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer.

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Cancer Prevention Research 2, 1015, December 1, 2009. doi: 10.1158/1940-6207.CAPR-09-0099

Effects of Chlorophyll and Chlorophyllin on Low-Dose Aflatoxin B1 Pharmacokinetics in Human Volunteers

Carole Jubert1, John Mata2, Graham Bench4, Roderick Dashwood1,3, Cliff Pereira3, William Tracewell5, Kenneth Turteltaub4, David Williams1,3 and George Bailey1,3

Authors’ Affiliations: 1 Linus Pauling Institute, 2 Biomedical Sciences, and 3 Environmental Health Sciences Center, Oregon State University, Corvallis Oregon; 4 Lawrence Livermore National Laboratory, Livermore California; and 5 Cephalon, Inc., West Chester Pennsylvania

Chlorophyll (Chla) and chlorophyllin (CHL) were shown previously to reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings were partially extended to humans, where CHL reduced excretion of aflatoxin B1 (AFB1)-DNA repair products in Chinese unavoidably exposed to dietary AFB1. However, neither AFB1 pharmacokinetics nor Chla effects were examined. We conducted an unblinded crossover study to establish AFB1 pharmacokinetic parameters among four human volunteers, and to explore possible effects of CHL or Chla cotreatment in three of those volunteers. For protocol 1, fasted subjects received an Institutional Review Board–approved dose of 14C-AFB1 (30 ng, 5 nCi) by capsule with 100 mL water, followed by normal eating and drinking after 2 hours. Blood and cumulative urine samples were collected over 72 hours, and 14C- AFB1 equivalents were determined by accelerator mass spectrometry. Protocols 2 and 3 were similar except capsules also contained 150 mg of purified Chla or CHL, respectively. Protocols were repeated thrice for each volunteer. The study revealed rapid human AFB1 uptake (plasma ka, 5.05 ± 1.10 h–1; Tmax, 1.0 hour) and urinary elimination (95% complete by 24 hours) kinetics. Chla and CHL treatment each significantly impeded AFB1 absorption and reduced Cmax and AUCs (plasma and urine) in one or more subjects. These initial results provide AFB1 pharmacokinetic parameters previously unavailable for humans, and suggest that Chla or CHL co-consumption may limit the bioavailability of ingested aflatoxin in humans, as they do in animal models.