Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo
Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo
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DOI：
10.1093/carcin/bgn161
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发表时间：
2008-11-01
期刊：
影响因子：
4.7
通讯作者：
Helferich, William G.
中科院分区：
文献类型：
--
作者：
Ju, Young H.;Doerge, Daniel R.;Helferich, William G.
染料木黄酮（GEN），一种大豆黄酮，在绝经后乳腺癌的临床前小鼠模型中刺激雌激素依赖性人肿瘤细胞（MCF-7）的生长。抗雌激素和芳香化酶抑制剂是雌激素依赖性乳腺癌的一线治疗药物。我们已经证明，饮食GEN可以否定他莫昔芬的抑制作用。在这项研究中，我们评估了饮食GEN（在250-1000 p. p.m.在美国营养研究所93生长饮食）和芳香酶抑制剂来曲唑（LET）的相互作用，在芳香酶表达的乳腺癌异种移植模型（MCF-7 Ca）的存在和不存在的底物雄烯二酮（AD）的肿瘤生长。饮食GEN（250和500 p. p.m.）或植入AD刺激MCF-7 Ca肿瘤生长。植入LET抑制AD刺激的MCF-7 Ca肿瘤生长。在存在AD和LET的情况下，饮食GEN（250、500和1000 p. p.m.）以剂量依赖方式逆转LET的抑制作用。测量子宫湿重、血浆雌二醇（E-2）水平（酶联免疫吸附测定法）和总血浆GEN和LET水平（液相色谱-电喷雾/串联质谱法）。Ki-67（细胞增殖），芳香化酶和pS2蛋白的表达在肿瘤中进行了评估，使用免疫组化（IHC）分析。总之，饮食GEN增加了卵巢切除小鼠中植入的MCF-7 Ca肿瘤的生长，并且还可以否定LET对MCF-7 Ca肿瘤生长的抑制作用。这些发现是重要的，因为表达芳香化酶并合成雌激素的肿瘤是芳香化酶治疗的良好候选者，饮食和GEN可以逆转LET对肿瘤生长的抑制作用，并对乳腺癌治疗产生不利影响。服用LET治疗的雌激素依赖性乳腺癌绝经后妇女应谨慎食用饮食GEN。
Genistein (GEN), a soy isoflavone, stimulates growth of estrogen-dependent human tumor cells (MCF-7) in a preclinical mouse model for postmenopausal breast cancer. Antiestrogens and aromatase inhibitors are frontline therapies for estrogen-dependent breast cancer. We have demonstrated that dietary GEN can negate the inhibitory effect of tamoxifen. In this study, we evaluated the interaction of dietary GEN (at 250-1000 p.p.m. in the American Institute of Nutrition 93 growth diet) and an aromatase inhibitor, letrozole (LET), on the growth of tumors in an aromatase-expressing breast cancer xenograft model (MCF-7Ca) in the presence and absence of the substrate androstenedione (AD). Dietary GEN (250 and 500 p.p.m.) or implanted AD stimulated MCF-7Ca tumor growth. Implanted LET inhibited AD-stimulated MCF-7Ca tumor growth. In the presence of AD and LET, dietary GEN (250, 500 and 1000 p.p.m.) reversed the inhibitory effect of LET in a dose-dependent manner. Uterine wet weight, plasma estradiol (E-2) levels (enzyme-linked immunosorbent assay) and total plasma GEN and LET levels (liquid chromatography-electrospray/tandem mass spectrometry) were measured. Ki-67 (cellular proliferation), aromatase and pS2 protein expression in tumors were evaluated using immunohistochemical (IHC) analysis. In conclusion, dietary GEN increased the growth of MCF-7Ca tumors implanted in ovariectomized mice and could also negate the inhibitory effect of LET on MCF-7Ca tumor growth. These findings are significant because tumors, which express aromatase and synthesize estrogen, are good candidates for aromatase therapy dietary and GEN can reverse the inhibitory effect of LET on tumor growth and adversely impact breast cancer therapy. Caution is warranted for consumption of dietary GEN by postmenopausal women with estrogen-dependent breast cancer taking LET treatment.