Shao Z M, Wu J, Shen Z Z, Barsky S H
Department of Surgery, Cancer Hospital/Cancer Institute, Shanghai Medical University, People's Republic of China.
Cancer Res. 1998 Nov 1;58(21):4851-7.
Dietary genistein, a natural flavone compound found in soy, has been proposed to be responsible for the low rate of breast cancer in Asian women. The cellular mechanisms of genistein's chemopreventive effects in vio have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both estrogen receptor-positive and -negative human breast carcinoma cells through G2-M arrest, induction of p21WAF1/CIP1 expression, and apoptosis. Because chemopreventive effects need not be limited to antiproliferation, we decided to examine whether genistein exerted other suppressive effects on breast carcinoma progression. Genistein inhibited invasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was characterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former of which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissue inhibitor of metalloproteinase-1 were also demonstrated in in vivo studies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In these xenograft studies, genistein inhibited tumor growth, stimulated apoptosis, and upregulated p21WAF1/CIP1 expression. In the MDA-MB-231 xenograft, genistein also inhibited angiogenesis by decreasing vessel density and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta1. These in vitro and in vivo studies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevention is pleiotropic.
膳食染料木黄酮是一种存在于大豆中的天然黄酮类化合物，有人认为它是亚洲女性乳腺癌发病率低的原因。染料木黄酮在体内的化学预防作用的细胞机制在很大程度上尚未得到探索。在我们之前的研究中，我们发现染料木黄酮通过G2-M期阻滞、诱导p21WAF1/CIP1表达和诱导凋亡，对雌激素受体阳性和阴性的人乳腺癌细胞均具有显著的抗增殖作用。由于化学预防作用不一定局限于抗增殖，我们决定研究染料木黄酮是否对乳腺癌进展具有其他抑制作用。染料木黄酮在体外抑制MCF-7和MDA-MB-231细胞的侵袭。这种抑制作用的特征是基质金属蛋白酶（MMP）-9的下调和金属蛋白酶组织抑制剂-1的上调，其中前者在MMP-9启动子的激活蛋白-1位点受到转录调控。在MDA-MB-231和MCF-7细胞的裸鼠异种移植体内研究中也证实了染料木黄酮对MMP-9和金属蛋白酶组织抑制剂-1的体外作用。在这些异种移植研究中，染料木黄酮抑制肿瘤生长，刺激凋亡，并上调p21WAF1/CIP1表达。在MDA-MB-231异种移植中，染料木黄酮还通过降低血管密度以及降低血管内皮生长因子和转化生长因子-β1的水平来抑制血管生成。这些体外和体内研究表明，染料木黄酮对乳腺癌细胞具有多种抑制作用，提示其化学预防机制具有多效性。
