Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice
Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice
复制标题
DOI：
10.1093/jn/131.11.2957
复制
发表时间：
2001-11-01
影响因子：
4.2
通讯作者：
Helferich, WG
中科院分区：
文献类型：
--
作者：
Ju, YH;Allred, CD;Helferich, WG
以前我们的实验室已经表明，大豆异黄酮，染料木素，刺激生长的人乳腺癌（MCF-7）细胞在体内和体外。在这项研究中，在植入MCF-7细胞的卵巢切除的无胸腺裸鼠中，在饮食中125至1，000 μ g/g的生理可实现浓度范围内进行染料木黄酮的剂量反应分析。我们假设，染料木黄酮在这个浓度范围内可以刺激剂量依赖性的乳腺肿瘤生长，细胞增殖和雌激素反应的pS2基因诱导。每周监测肿瘤大小和体重。在研究完成时，我们使用掺入BrdU分析肿瘤的细胞增殖，使用北方印迹分析肿瘤的pS2表达，并且使用液相色谱-同位素稀释质谱法（LC-ES/MS）分析血浆中的总染料木黄酮水平。膳食染料木黄酮（大于或等于250 kg/g）以剂量依赖性方式增加肿瘤大小[250 μ g/g组为阴性对照（NC）组的8.4倍，500 μ g/g组为12.0倍，1，000 μ g/g组为20.2倍，阳性对照（PC）组为23.2倍]。在250 μ g/g和高于250 μ g/g时，染料木黄酮显著增加了增殖细胞的百分比（250 μ g/g是NC组的5.3倍，500 μ g/g是5.6倍，1,000 μ g/g是5.0倍，PC组是4.8倍）。pS2 mRNA的表达也随着膳食染料木黄酮水平的增加而显著增加（500 μ g/g组是NC组的11.25倍，1，000 μ g/g组是NC组的15.84倍）。在喂食125和1，000 μ g/g染料木黄酮的小鼠中，总血浆染料木黄酮浓度在0.39和3.36 μ mol/L之间。总之，以生理浓度的染料木黄酮进行饮食治疗产生足以刺激雌激素效应的染料木黄酮的血液水平，所述雌激素效应例如在无胸腺小鼠中以与体外观察到的相似的剂量响应方式的乳腺肿瘤生长、细胞增殖和pS2表达。
Previously our laboratory has shown that the soy isoflavone, genistein, stimulates growth of human breast cancer (MCF-7) cells in vivo and in vitro. In this study, the dose-response analysis of genistein at the physiologically achievable concentration range between 125 and 1,000 mug/g in the diet was conducted in ovariectomized athymic nude mice implanted with MCF-7 cells. We hypothesized that genistein at this concentration range can stimulate dose-dependently the breast tumor growth, cell proliferation and an estrogen-responsive pS2 gene induction. Tumor size and body weight were monitored weekly. At completion of the study, we analyzed cellular proliferation of tumors using incorporation of BrdU, pS2 expression of tumors using a Northern blot analysis and total genistein level in plasma using liquid chromatography-isotope dilution mass spectrometry (LC-ES/MS). Dietary genistein (greater than or equal to 250 kg/g) increased tumor size in a dose-dependent manner [8.4x the negative control (NC) group in the 250 mug/g group, 12.0x in the 500 mug/g group, 20.2x in the 1,000 mug/g group and 23.2x in the positive control (PC) group]. The percentage of proliferating cells was significantly increased by genistein at and above 250 mug/g (5.3x the NC group in the 250 mug/g, 5.6x in the 500 mug/g, 5.0x in the 1,000 mug/g and 4.8x in the PC group). Expression of pS2 mRNA was also significantly increased with increasing dietary genistein levels (11.25x the NC group in the 500 mug/g group and 15.84x in the 1,000 mug/g group). Total plasma genistein concentrations were between 0.39 and 3.36 mu mol/L in mice fed between 125 and 1,000 mug/g genistein. In conclusion, dietary treatment with genistein at physiological concentrations produces blood levels of genistein sufficient to stimulate estrogenic effects, such as breast tumor growth, cellular proliferation and pS2 expression in athymic mice in a dose-responsive manner similar to that seen in vitro.