Randomized dose-response trial of n–3 fatty acids in hormone receptor negative breast cancer survivors — Impact on breast adipose oxylipin and DNA methylation patterns

Authors: FRANKHOUSER, DAVID - City Of Hope National Medical Center; DEWEES, TODD - City Of Hope National Medical Center; SNODGRASS, ISABEL - City Of Hope National Medical Center; COLE, RACHEL - The Ohio State University; STECK, SARAH - The Ohio State University; THOMAS, DANIELLE - City Of Hope National Medical Center; KALU, CHIDIMMA - City Of Hope National Medical Center; BELURY, MARTHA - The Ohio State University; CLINTON, STEVEN - The Ohio State University; Newman, John; YEE, LISA - City Of Hope National Medical Center

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/21/2025
Publication Date: 4/25/2025
Citation: Frankhouser, D.E., DeWees, T., Snodgrass, I.F., Cole, R.M., Steck, S., Thomas, D., Kalu, C., Belury, M.A., Clinton, S.K., Newman, J.W., Yee, L.D. 2025. Randomized dose-response trial of n–3 fatty acids in hormone receptor negative breast cancer survivors — Impact on breast adipose oxylipin and DNA methylation patterns. The American Journal of Clinical Nutrition. 122(1):70-82. https://doi.org/10.1016/j.ajcnut.2025.04.021.
DOI: https://doi.org/10.1016/j.ajcnut.2025.04.021

Interpretive Summary: Increasing evidence indicates unique susceptibility of estrogen receptor and progesterone receptor negative (ERPR-) breast cancer to dietary fat amount and type. Dietary long-chain n-3 polyunsaturated fatty acids like those found in cold water fatty fish can reduce ERPR- breast cancer risk and may change breast tissue levels of these fats and some of their anti-inflammatory metabolites. We fed 51 ERPR(-) breast cancer survivors either 5g or 1g of long-chain n-3 polyunsaturated fatty acids for 1yr and measured breast tissue and blood levels of these fats and their metabolites in tissue, along with changes in gene methylation. Observed lipid changes were largely stable after 6mo. The 5g/d dose was more potent and associated with triglyceride lowering and changes in methylation of genes involved in lipid metabolism, partially explaining the mechanisms by which high-dose EPA+DHA may prevent ERPR(-) breast cancer.

Technical Abstract: Increasing evidence indicates unique susceptibility of estrogen receptor and progesterone receptor negative (ERPR-) breast cancer to dietary fat amount and type. Dietary long-chain n-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acid profiles and downstream bioactive metabolites to counteract pro-inflammatory, pro-carcinogenic signaling in the mammary microenvironment. We conducted a 12-month randomized controlled, double-blind trial of ~5g/d vs ~1g/d DHA+EPA supplementation in 51 ERPR(-) breast cancer survivors. While both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, 5g/d was more potent (p<0.001). The 5g/d dose also reduced plasma triglycerides from baseline (p =0.008). Breast adipose oxylipins showed dose-dependent increases in DHA- and EPA-metabolites. Distinct DNA methylation patterns in adipose tissue suggest potential downregulation of aberrant lipid metabolism pathways unique to 5g/d. These data provide evidence of both metabolic and epigenetic effects of n-3 PUFAs in breast adipose tissue, elucidating novel mechanisms of action for high-dose EPA+DHA-mediated prevention of ERPR(-) breast cancer.