Frankhouser David E, DeWess 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 91010.
Department of Surgery, City of Hope, Duarte CA 91010.
medRxiv. 2024 Sep 16:2024.09.16.24313691. doi: 10.1101/2024.09.16.24313691.
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 polyunsaturated fatty acids (PUFAs), such as 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.
To determine effects of ~1 to 5 g/d EPA+DHA over 12 months on breast adipose fatty acid and oxylipin profiles in women with ERPR(-) breast cancer, a high-risk molecular subtype.
We conducted a 12-month randomized controlled, double-blind clinical trial of ~5g/d vs ~1g/d DHA+EPA supplementation in women within 5 years of completing standard therapy for ERPR(-) breast cancer Stages 0-III. Blood and breast adipose tissue specimens were collected every 3 months for biomarker analyses including fatty acids by gas chromatography, oxylipins by LC-MS/MS, and DNA methylation by reduced-representation bisulfite sequencing (RRBS).
A total of 51 participants completed the 12-month intervention. Study treatments were generally well-tolerated. While both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5g/d supplement was more potent (n =51, p <0.001). The 5g/d dose also reduced plasma triglycerides from baseline (p =0.008). Breast adipose oxylipins at 0, 6, and 12 months showed dose-dependent increases in unesterified and esterified DHA and EPA metabolites (n =28). Distinct DNA methylation patterns in adipose tissue after 12 months were identified, with effects unique to the 5g/d dose group (n =17).
Over the course of 1 year, EPA+DHA dose-dependently increased concentrations of these fatty acids and their derivative oxylipin metabolites, producing differential DNA methylation profiles of gene promoters involved in metabolism-related pathways critical to ERPR(-) breast cancer development and progression. 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.
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组织中的脂肪酸谱和下游生物活性代谢物，以抵消乳腺微环境中的促炎、促癌信号。
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）女性乳腺脂肪组织中的脂肪酸和氧化脂质谱的影响。
我们对完成0-III期ERPR（-）乳腺癌标准治疗后5年内的女性进行了一项为期12个月的随机对照双盲临床试验，比较每天补充约5克与约1克DHA+EPA的效果。每3个月采集一次血液和乳腺脂肪组织样本，进行生物标志物分析，包括通过气相色谱法分析脂肪酸、通过液相色谱-串联质谱法分析氧化脂质，以及通过简化代表性亚硫酸氢盐测序（RRBS）分析DNA甲基化。
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组织、红细胞和血浆中的n-3多不饱和脂肪酸相对于基线水平有所增加，但每天补充5克的效果更显著（n = 51，p <0.001）。每天5克的剂量还使血浆甘油三酯相对于基线水平降低（p = 0.008）。在0、6和12个月时，乳腺脂肪组织中的氧化脂质显示未酯化和酯化的DHA和EPA代谢物呈剂量依赖性增加（n = 28）。在12个月后，在脂肪组织中发现了不同的DNA甲基化模式，其中每天5克剂量组具有独特的影响（n = 17）。
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物的浓度，产生了参与对ERPR（-）乳腺癌发展和进展至关重要的代谢相关途径的基因启动子的差异DNA甲基化谱。这些数据提供了n-3多不饱和脂肪酸在乳腺脂肪组织中的代谢和表观遗传效应的证据，阐明了高剂量EPA+DHA介导的预防ERPR（-）乳腺癌的新作用机制。
