Frankhouser David E, DeWees Todd, Snodgrass Isabel F, Cole Rachel M, Steck Sarah, Thomas Danielle, Kalu Chidimma, Belury Martha A, Clinton Steven K, Newman John W, Yee Lisa D
Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA.
Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA; Department of Surgery, City of Hope, Duarte, CA.
Am J Clin Nutr. 2025 Jul;122(1):70-82. doi: 10.1016/j.ajcnut.2025.04.021. Epub 2025 Apr 25.
Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative [ERPR(-)] breast cancer to dietary fat amount and type. Dietary n-3 (ω-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acids and downstream metabolites to counteract procarcinogenic signaling in the mammary microenvironment.
We aimed to determine effects of ∼1 to 5 g/d EPA+DHA over 12 mo on breast adipose fatty acid and oxylipin profiles in survivors of ERPR(-) breast cancer, a high-risk molecular subtype.
We conducted a proof-of-concept 12-mo randomized double-blind trial comparing ∼5 g/d and ∼1 g/d EPA+DHA supplementation in females within 5 y of completing standard therapy for ERPR(-) breast cancer Stages 0 to III. Blood and breast adipose tissue specimens were collected every 3 mo for fatty acid, oxylipin, and DNA methylation (DNAm) analyses.
A total of 51 participants completed the 12-mo intervention. Study treatments were generally well tolerated. Although both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5 g/d supplement was more potent with differences (% total fatty acids) of 0.76 (95% confidence interval [CI]: 0.56, 0.96), 6.25 (95% CI: 5.02, 7.48), and 5.89 (95% CI: 4.53, 7.25), respectively. The 5 g/d dose also reduced plasma triglycerides from baseline, with changes (mg/dL) of 27.38 (95% CI: 10.99, 43.78) and 24.58 (95% CI: 9.05, 40.10) at 6 and 12 months, respectively. Breast adipose oxylipins showed dose-dependent increases in DHA and EPA metabolites. Distinct DNAm patterns in adipose tissue after 12 mo suggest potential downregulation of aberrant lipid metabolism pathways at the 5 g/d dose.
Over 1 y, EPA+DHA dose-dependently increased breast adipose concentrations of these fatty acids and their derivative oxylipin metabolites and produced differential DNAm profiles involved in metabolism-related pathways critical to ERPR(-) breast cancer development. This distinct metabolic and epigenetic modulation of the breast microenvironment is achievable with high-dose n-3 PUFA supplementation. This trial was registered at clinicaltrials.gov as NCT02295059.
越来越多的证据表明，雌激素受体和孕激素受体阴性[ERPR(-)]乳腺癌对膳食脂肪的量和类型具有独特的易感性。膳食中的n-3（ω-3）多不饱和脂肪酸（PUFA），如二十二碳六烯酸（DHA）和二十碳五烯酸（EPA），可能会调节乳腺脂肪中的脂肪酸及其下游代谢产物，以抵消乳腺微环境中的促癌信号。
我们旨在确定在12个月内每天摄入约1至5克EPA+DHA对ERPR(-)乳腺癌（一种高危分子亚型）幸存者乳腺脂肪中的脂肪酸和氧化脂质谱的影响。
我们进行了一项为期12个月的概念验证随机双盲试验，比较了在完成0至III期ERPR(-)乳腺癌标准治疗后5年内的女性中，每天补充约5克和约1克EPA+DHA的效果。每3个月采集血液和乳腺脂肪组织样本，进行脂肪酸、氧化脂质和DNA甲基化（DNAm）分析。
共有51名参与者完成了12个月的干预。研究治疗一般耐受性良好。虽然两种剂量都使乳腺脂肪、红细胞和血浆中的n-3 PUFA相对于基线水平有所增加，但每天5克的补充剂效果更强，差异（占总脂肪酸的百分比）分别为0.76（95%置信区间[CI]：0.56，0.96）、6.25（95%CI：5.02，7.48）和5.89（95%CI：4.53，7.25）。每天5克的剂量还使血浆甘油三酯相对于基线水平降低，在6个月和12个月时的变化（毫克/分升）分别为27.38（95%CI：10.99，43.78）和24.58（95%CI：9.05，40.10）。乳腺脂肪中的氧化脂质显示出DHA和EPA代谢产物的剂量依赖性增加。12个月后脂肪组织中不同的DNAm模式表明，每天5克的剂量可能会下调异常脂质代谢途径。
在1年的时间里，EPA+DHA剂量依赖性地增加了这些脂肪酸及其衍生的氧化脂质代谢产物在乳腺脂肪中的浓度，并产生了与ERPR(-)乳腺癌发展关键的代谢相关途径有关的不同DNAm谱。通过高剂量补充n-3 PUFA可以实现对乳腺微环境的这种独特的代谢和表观遗传调节。该试验已在clinicaltrials.gov上注册，注册号为NCT02295059。
