Cancer Prevention and Control
Members in the Cancer Prevention and Control Program conduct a broad scope of research that encompasses basic studies of carcinogenesis, preclinical and clinical translational research, behavioral and epidemiological studies, as well as population-based genetic research. Over the past year, Program 6 members have produced 95 peer-reviewed publications, many in high impact journals. Program 6 members are highly interactive as evidenced by 22% of publications being interprogrammatic and 17% intraprogrammatic.
Research Highlights
Neural substrates of alcohol-induced smoking urge in heavy drinking nondaily smokers
A strong link exists between cigarette smoking and alcohol use. Neuroimaging studies have provided initial clues on potential mechanisms underlying smoking and alcohol-induced brain activity, which may involve the ventral striatum. Andrea King, PhD, in a double-blinded, placebo-controlled, crossover study, used functional magnetic resonance imaging to examine the response to smoking cues in heavy drinking nondaily social smokers after consuming an intoxicating dose of alcohol or placebo. Reactivity in the ventral striatum and other brain regions was examined during exposure to visual smoking versus nonsmoking control cues. The consumption of a moderately intoxicating oral dose of alcohol increased the desire to smoke and amplified ventral striatum reactivity in response to smoking compared with control cues. Alcohol also dampened orbitofrontal activity across both cue types, whereas dorsolateral prefrontal and anterior cingulate cortex activation to smoking cues was not affected by alcohol. These results provide a potential neurobiological mechanism to explain the co-abuse of these two commonly consumed cancer causing agents. (King et al., Neuropsychopharmacology 35:692-701, 2010)
Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study
An estimated 35-77 million people in Bangladesh are chronically exposed to arsenic through drinking water. Exposure to arsenic has been associated with several cancers as well as peripheral vascular disease. However, the association between arsenic exposure and mortality rate has not been prospectively investigated. Habibul Ahsan, MBBS, MMedSc, and Brandon Pierce, PhD, used data from the Health Effects of Arsenic Longitudinal Study (HEALS) to prospectively assess whether chronic and recent changes in arsenic exposure are associated with all-cause and chronic-disease mortalities in a Bangladeshi population. The HEALS population includes 11,746 clinically-assessed individuals who were interviewed in person. The risk of all-cause mortality and chronic-disease mortality increased with increasing levels of chronic arsenic exposure, measured by total arsenic concentrations in the urine. These data emphasize the urgent need to investigate solutions to mitigate the resulting health effects from chronic arsenic exposure. (Argos et al., Lancet 376:252-258, 2010)
Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome
The Wnt/beta-catenin pathway has been implicated in mammary tumorigenesis, but its importance in human breast cancer has not been clearly established. Dezheng Huo, MD, PhD, and Olufunmilayo Olopade, MBBS, FACP, along with Kathleen Goss, PhD (Program 1 - Molecular Mechanisms of Cancer), investigated Wnt/beta-catenin activation in distinct breast cancer subtypes. Using invasive and in situ breast cancer tissue microarrays containing luminal A, luminal B, HER2+/ER-, and basal-like breast cancers, beta-catenin subcellular localization was examined. Both cytosolic and nuclear beta-catenin were more frequently observed in basal-like invasive breast cancers and associated with markers of the basal-like phenotype, including stem cell enrichment and HER2 negativity. Subcellular localization of beta-catenin was also predictive of poor outcome and more frequently observed in tumors from black patients. Collectively, these data indicate that activation of the Wnt/beta-catenin pathway is an important feature of basal-like breast cancers, is predictive of worse overall survival, and may serve as a potential pharmacological target for this breast cancer subtype. (Khramtsov et al., Am J Pathol 176:2911-2920, 2010)
Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci
Pharmacogenomics has employed both candidate gene studies and GWAS to identify loci associated with drug response and/or toxicity. While GWAS allows for the simultaneous, unbiased testing of millions of SNPs, functional information is absent for the majority of implicated loci. Nancy Cox, PhD, along with Drs. Dolan and Huang (Program 4 - Pharmacogenomics and Experimental Therapeutics), evaluated the genomic regions and functional categories of drug susceptibility-associated SNPs for six different anticancer agents. Chemo-therapeutic drug susceptibility-associated SNPs were more likely to be eQTLs and associated with the transcriptional expression level of multiple genes as potential master regulators. This enrichment is not present for other traditionally important SNP functional categories. These findings highlight the importance of genetic variations in affecting transcript abundance in elucidating the genetic determinants of chemo-therapeutic drug susceptibility. (Gamazon et al., PNAS 107:9287-9292, 2010)
