Plos One, 2013, 8(1):e54369-e54369.

Epigenetic Regulation of Multiple Tumor-Related Genes Leads to Suppression of Breast Tumorigenesis by Dietary Genistein

Yuanyuan Li, Huaping Chen, Tabitha M. Hardy, et al

Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; et al

Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

美国《公共科学图书馆一》，2013年1月

由膳食性金雀异黄素对多种肿瘤相关基因的表观遗传调控导致了乳腺癌的抑制

李媛媛，陈华平，塔比莎 M  哈迪，等

美国阿拉巴马大学伯明翰分校生物学院等

乳腺癌是女性最致命的疾病之一；然而，确切的治病因素目前还不清楚。金雀异黄素 (GE)，一种在大豆中发现的天然异黄酮，被认为是一种强效的乳腺癌化学预防试剂。GE 抑制乳腺癌的最重要机制之一可能涉及其对表观遗传过程的潜在影响允许乳腺肿瘤异常的表观遗传表现逆转。为了探究 GE对乳腺癌的表观遗传调控，我们监测了既定的乳腺癌转化体系中几种关键的肿瘤相关基因的表观遗传变化。我们的研究结果表明在前期乳腺癌细胞和乳腺癌细胞中， GE以剂量依赖的方式 明显抑制细胞生长，而它对人体正常乳腺上皮细胞的影响不大。此外，GE 治疗增加了两种重要的肿瘤抑制基因的表达，p21(WAF1) (p21) 和 p16(INK4a) (p16)，虽然它降低了两种肿瘤促进基因 BMI1 和 c-MYC的表达。GE 治疗导致了p21 和 p16 的启动子组蛋白修饰的 改变，以及 c-MYC-BMI1 混合物绑定到p16 启动子的能力有利于GE 诱导的肿瘤抑制基因的表观遗传活化。此外，口服 GE 饮食预防乳腺肿瘤发生并抑制小鼠移植乳腺癌的发展。我们的结果表明，金雀异黄素可能通过影响组蛋白修饰的p21 和 p16的表观遗传调控来抑制早期乳腺肿瘤的发生，以及将BMI1-c-MYC聚集到这些基因的启动子的调控区。这些研究有助于在预防乳腺癌方面更有效地利用大豆产物，同时也有利于阐明早期乳腺癌的机制。