Abstract
BackgroundPrevious studies of fatty acids and breast cancer risk have shown mixed results, which may be due in part to tumor heterogeneity. Prior research has also illustrated an important role of specific fatty acids in immune regulation, T cell function, and inflammation, indicating that the effects of specific fatty acids on breast cancer risk may vary by tumor expression of immuno-inflammatory markers. We therefore aimed to evaluate the relationships between prediagnostic erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers (CD4, CD8, CD20, CD163, COX-2) and fatty acid synthase (FAS).MethodsWe conducted a matched case-control study nested within the Nurses’ Health Study II (n = 235 cases and 235 controls). Blood samples were collected from 1996 to 1999. Tumor tissue blocks were collected for cases diagnosed after blood collection and through 2006. Unconditional nominal polytomous logistic regression adjusted for matching factors and potential confounders was used to assess whether associations between fatty acids and breast cancer risk varied by tumor expression subtype, ascertained via immunohistochemistry. Odds ratios (OR) and 95% confidence intervals (CI) were estimated separately by tumor expression subtype using unconditional logistic regression.ResultsAssociations between fatty acids and breast cancer risk did not vary substantially by tumor CD4, CD20, CD163, or COX-2. However, n-3 polyunsaturated fatty acids (PUFAs) were inversely associated with CD8low but not CD8high cancers (CD8low ORT3 vs T1 = 0.45, 95% CI 0.23–0.87, Ptrend = 0.02; CD8high ORT3 vs T1 = 1.19, 95% CI 0.62–2.26, Ptrend = 0.62; Phet = 0.04). n-6 PUFAs were suggestively inversely associated with CD8high but not CD8low cancers (CD8high ORT3 vs T1 = 0.61, 95% CI 0.32–1.14, Ptrend = 0.11; CD8low ORT3 vs T1 = 1.63, 95% CI 0.87–3.04, Ptrend = 0.12; Phet = 0.02). Trans fatty acids were positively associated with FAShigh but not FASlow tumors (FAShigh ORT3 vs T1 = 2.94, 95% CI 1.46–5.91, Ptrend = 0.002; FASlow ORT3 vs T1 = 0.99, 95% CI 0.52–1.92, Ptrend = 0.97; Phet = 0.01).ConclusionResults indicate that the effects of n-3 PUFAs, n-6 PUFAs, and trans fatty acids on breast cancer risk may vary by tumor tissue expression subtypes. Findings suggest potential immuno-modulatory and FAS-mediated mechanisms.
Highlights
Previous studies of fatty acids and breast cancer risk have shown mixed results, which may be due in part to tumor heterogeneity
In a recent analysis within the Nurses’ Health Study II (NHSII), we found that some prediagnostic erythrocyte membrane fatty acids, including several trans fatty acids, saturated fatty acids, dairy-derived fatty acids, and n-3 polyunsaturated fatty acids (PUFAs), were associated with breast cancer risk among obese/overweight women, but not among women overall [17]
Our epidemiologic findings provide greater credence to the hypothesis that n-3 PUFAs may reduce breast cancer risk through these immuno-modulatory mechanisms because cytotoxic CD8 T cells have antitumorigenic properties [27], and tumors that arise in an immune microenvironment with a dearth of CD8 cells may derive greater benefit from the anti-inflammatory, immuno-modulatory effects of n-3 PUFAs
Summary
Previous studies of fatty acids and breast cancer risk have shown mixed results, which may be due in part to tumor heterogeneity. Prior research has illustrated an important role of specific fatty acids in immune regulation, T cell function, and inflammation, indicating that the effects of specific fatty acids on breast cancer risk may vary by tumor expression of immuno-inflammatory markers. We aimed to evaluate the relationships between prediagnostic erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers (CD4, CD8, CD20, CD163, COX-2) and fatty acid synthase (FAS). Growing experimental evidence indicates that some fatty acids may influence breast cancer risk through a variety of immuno-inflammatory mechanisms. The effects of fatty acids on breast cancer risk may differ by type of fatty acid and by breast tumor expression subtype, underscoring the importance of further characterizing associations by tumor subtype
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