Zhang Xiyuan, Cook Katherine L, Warri Anni, Cruz Idalia M, Rosim Mariana, Riskin Jeffrey, Helferich William, Doerge Daniel, Clarke Robert, Hilakivi-Clarke Leena
Department of Oncology, Georgetown University, Washington, District of Columbia.
Department of Surgical Sciences, Wake Forest University, Winston-Salem, North Carolina.
Clin Cancer Res. 2017 Feb 1;23(3):814-824. doi: 10.1158/1078-0432.CCR-16-1735.
Whether it is safe for estrogen receptor-positive (ER+) patients with breast cancer to consume soy isoflavone genistein remains controversial. We compared the effects of genistein intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen therapy using a preclinical model.
Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm genistein from postnatal day 15 onward (lifetime genistein). Mammary tumors were induced with 7,12-dimethylbenz(a)anthracene (DMBA), after which a group of control diet-fed rats were switched to genistein diet (adult genistein). When the first tumor in a rat reached 1.4 cm in diameter, tamoxifen was added to the diet and a subset of previously only control diet-fed rats also started genistein intake (post-diagnosis genistein).
Lifetime genistein intake reduced de novo resistance to tamoxifen, compared with post-diagnosis genistein groups. Risk of recurrence was lower both in the lifetime and in the adult genistein groups than in the post-diagnosis genistein group. We observed downregulation of unfolded protein response (UPR) and autophagy-related genes (GRP78, IRE1α, ATF4, and Beclin-1) and genes linked to immunosuppression (TGFβ and Foxp3) and upregulation of cytotoxic T-cell marker CD8a in the tumors of the lifetime genistein group, compared with controls, post-diagnosis, and/or adult genistein groups.
Genistein intake mimicking Asian consumption patterns improved response of mammary tumors to tamoxifen therapy, and this effect was linked to reduced activity of UPR and prosurvival autophagy signaling and increased antitumor immunity. Clin Cancer Res; 23(3); 814-24. ©2017 AACR.
雌激素受体阳性（ER+）乳腺癌患者食用大豆异黄酮染料木黄酮是否安全仍存在争议。我们使用临床前模型，比较了模拟亚洲人（终生）或白种人（成年期）摄入模式摄入染料木黄酮与在他莫昔芬治疗期间开始摄入染料木黄酮的效果。
从出生后第15天起，给雌性Sprague-Dawley大鼠喂食补充了0（对照饮食）或500 ppm染料木黄酮的AIN93G饮食（终生染料木黄酮）。用7,12-二甲基苯并(a)蒽（DMBA）诱导乳腺肿瘤，之后将一组喂食对照饮食的大鼠换成染料木黄酮饮食（成年染料木黄酮）。当大鼠体内的第一个肿瘤直径达到1.4 cm时，在饮食中添加他莫昔芬，并且一组之前只喂食对照饮食的大鼠也开始摄入染料木黄酮（诊断后染料木黄酮）。
与诊断后染料木黄酮组相比，终生摄入染料木黄酮降低了对他莫昔芬的新生耐药性。终生和成年染料木黄酮组的复发风险均低于诊断后染料木黄酮组。与对照组、诊断后和/或成年染料木黄酮组相比，我们在终生染料木黄酮组的肿瘤中观察到未折叠蛋白反应（UPR）和自噬相关基因（GRP78、IRE1α、ATF4和Beclin-1）以及与免疫抑制相关的基因（TGFβ和Foxp3）的下调，以及细胞毒性T细胞标志物CD8a的上调。
模拟亚洲人消费模式摄入染料木黄酮可改善乳腺肿瘤对他莫昔芬治疗的反应，这种效果与UPR和促生存自噬信号活性降低以及抗肿瘤免疫力增强有关。临床癌症研究；23(3)；814 - 24。©2017美国癌症研究协会。
