Faculty Bibliography

BACKGROUND AND AIMS: Investigation of microbe-metabolite relationships in the gut is needed to understand and potentially reduce colorectal cancer (CRC) risk. METHODS: Microbiota and metabolomics profiling were performed on lyophilized feces from 42 CRC cases and 89 matched controls. Multivariable logistic regression was used to identify statistically independent associations with CRC. First principal coordinate-component pair (PCo1-PC1) and false discovery rate (0.05)-corrected P-values were calculated for 116,000 Pearson correlations between 530 metabolites and 220 microbes in a sex*case/control meta-analysis. RESULTS: Overall microbe-metabolite PCo1-PC1 was more strongly correlated in cases than in controls (Rho 0.606 vs 0.201, P = 0.01). CRC was independently associated with lower levels of Clostridia, Lachnospiraceae, p-aminobenzoate and conjugated linoleate, and with higher levels of Fusobacterium, Porphyromonas, p-hydroxy-benzaldehyde, and palmitoyl-sphingomyelin. Through postulated effects on cell shedding (palmitoyl-sphingomyelin), inflammation (conjugated linoleate), and innate immunity (p-aminobenzoate), metabolites mediated the CRC association with Fusobacterium and Porphyromonas by 29% and 34%, respectively. Overall, palmitoyl-sphingomyelin correlated directly with abundances of Enterobacteriaceae (Gammaproteobacteria), three Actinobacteria and five Firmicutes. Only Parabacteroides correlated inversely with palmitoyl-sphingomyelin. Other lipids correlated inversely with Alcaligenaceae (Betaproteobacteria). Six Bonferroni-significant correlations were found, including low indolepropionate and threnoylvaline with Actinobacteria and high erythronate and an uncharacterized metabolite with Enterobacteriaceae. CONCLUSIONS: Feces from CRC cases had very strong microbe-metabolite correlations that were predominated by Enterobacteriaceae and Actinobacteria. Metabolites mediated a direct CRC association with Fusobacterium and Porphyromonas, but not an inverse association with Clostridia and Lachnospiraceae. This study identifies complex microbe-metabolite networks that may provide insights on neoplasia and targets for intervention.

Higher intake of omega-3 relative to omega-6 polyunsaturated fatty acids (PUFAs) may reduce breast carcinogenesis via different metabolic pathways. The PUFA-breast cancer association remains inconclusive, thus, we hypothesized that interactions between the ratio of dietary omega-3:omega-6 intake and polymorphisms from PUFA-related metabolic pathways would help elucidate an association. Utilizing resources from the Long Island Breast Cancer Study Project, a population-based case-control study (n=1035 cases/1075 controls), we examined interactions between omega-3:omega-6 ratio and 18 polymorphisms of 15 genes. Compared to the putative lowest risk group (high omega-3:omega-6,low-risk FASL rs763110 CT/TT genotype), the odds ratio (OR) for breast cancer from unconditional logistic regression models was weakly increased for other exposure-genotype combinations (high omega-3:omega-6,high-risk FASL CC genotype, OR=1.18,95% confidence interval(CI)=0.90,1.53; low omega-3:omega-6,CT/TT genotype, OR=1.35,95%CI=1.09,1.66); but was approximately null for the putative highest risk group (low omega-3:omega-6,CC genotype; OR=1.06,95%CI=0.81,1.38). We observed an interaction between the omega-3:omega-6 ratio and FASL rs763110 on the additive scale [Relative Excess Risk Due to Interaction(RERI)=-0.47, 95%CI=-0.92,-0.02]. Interactions with other polymorphisms considered were not evident. Our findings suggest that the PUFA-breast cancer association may be modified by FASL. However, additional research is needed given this interaction may be due to chance and is inconsistent with our a priori biologic hypothesis.

PURPOSE: Experimental studies demonstrate that omega-3 polyunsaturated fatty acids (PUFAs) inhibit inflammatory eicosanoids generated by omega-6 PUFAs. Epidemiologic studies on dietary omega-3 PUFA intake show consistent inverse associations with breast cancer incidence among Asian populations, where omega-3, relative to omega-6, intake is high. In contrast, associations are inconsistent among Western populations, where intake of omega-3, relative to omega-6, is low. We hypothesized that examining interactions between omega-3 and omega-6 would help elucidate the PUFA-breast cancer association in the United States. METHODS: In a Long Island, New York, population-based study of 1463 breast cancer cases and 1500 controls, we estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression to examine interactions between omega-3 and omega-6 intake. RESULTS: We observed a super-additive interaction (relative excess risk due to interaction = 0.41; 95% confidence interval = 0.06-0.76) between omega-3 and omega-6 intake in association with breast cancer incidence, although the CIs for the joint exposure of low omega-3/high omega-6 compared to high omega-3/low omega-6 intake were wide (odds ratio = 1.20; 95% confidence interval = 0.85-1.69). CONCLUSIONS: Breast cancer risk reduction may be possible for U.S. women with dietary consumption of higher omega-3, which has anti-inflammatory properties, in concert with lower omega-6, which induces inflammation. Replication from future U.S.-based investigations is needed.

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.

BACKGROUND: In laboratory experiments, omega-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from omega-6 PUFA metabolism via competitive inhibition, and the omega-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary omega-3 PUFA intake benefits survival after breast cancer are limited and inconsistent. METHODS: The authors used resources from a population-based follow-up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire). Vital status was determined through 2011, yielding a median follow-up of 14.7 years and 485 deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression. RESULTS: All-cause mortality was reduced among women with breast cancer reporting the highest quartile of intake (compared with never) for tuna (HR, 0.71; 95% CI, 0.55-0.92), other baked/broiled fish (HR, 0.75; 95% CI, 0.58-0.97), and the dietary long-chain omega-3 PUFAs docosahexaenoic acid (HR, 0.71; 95% CI, 0.55-0.92) and eicosapentaenoic acid (HR, 0.75; 95% CI, 0.58-0.97). CONCLUSIONS: All-cause mortality was reduced by 16% to 34% among women with breast cancer who reported a high intake of fish and long-chain omega-3 PUFAs. Long-chain omega-3 PUFA intake from fish and other dietary sources may provide a potential strategy to improve survival after breast cancer. Cancer 2015. (c) 2015 American Cancer Society.

PURPOSE: Obesity is associated with increased bioavailability of estrogen, hyperinsulinemia, and chronic inflammation, all of which may promote tumor growth. Given DNA repair and oxidative stress pathways may work together with these mechanisms to influence carcinogenesis, we hypothesized that genetic variation in these pathways may modify the obesity-postmenopausal breast cancer (BC) association. METHODS: Resources from a population-based case-control study (990 cases and 970 controls) were used to construct logistic regression models. Body mass index (BMI, weight [kilogram]/height [square meter]) was assessed 1 year before reference date. We characterized interactions between BMI and 29 genetic polymorphisms in oxidative stress and DNA repair pathways. RESULTS: Age-adjusted odds ratios (95% confidence intervals) for postmenopausal BC were 1.24 (1.00-1.52) and 1.35 (1.09-1.71) for 25 >/= BMI < 30 and BMI >/= 30 kg/m(2), respectively. We observed multiplicative interactions (P