Mielnicki L M, Asch H L, Asch B B
Division of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
J Mammary Gland Biol Neoplasia. 2001 Apr;6(2):169-82. doi: 10.1023/a:1011356623442.
The production of heritable changes in gene expression is the driving force in the development and progression of breast cancer. Such changes can result from mutations or from epigenetic events such as hypermethylation of DNA and hypoacetylation of histones. Histone acetylation and DNA methylation are major determinants of chromatin structure, and chromatin structure is a primary regulator of gene transcription. Cancer cells frequently contain both mutated genes and genes with altered expression due to one or more epigenetic mechanisms. This review describes the epigenetic changes that disrupt normal chromatin architecture and modify the expression of key genes in breast cancer cells. The structural integrity of the latter genes is usually intact, but their expression has been substantially altered due to methylation in their promoter region or deacetylation of histones that interact with their promoter region or both mechanisms. Genes affected by epigenetic changes in breast cancers include HoxA5, p21WAF, gelsolin, BRCA1, BRCA2, E-cadherin, steroid hormone receptors, and retinoic acid receptor II. Because these epigenetic modifications are usually reversible by treatment with certain drugs, they represent vulnerabilities in the cancer cell that can be exploited as novel targets for new prevention and therapeutic strategies.
基因表达中可遗传变化的产生是乳腺癌发生和发展的驱动力。此类变化可能源于基因突变，也可能源于表观遗传事件，如DNA的高甲基化和组蛋白的低乙酰化。组蛋白乙酰化和DNA甲基化是染色质结构的主要决定因素，而染色质结构是基因转录的主要调节因子。癌细胞通常既含有突变基因，也含有由于一种或多种表观遗传机制而导致表达改变的基因。本综述描述了那些破坏正常染色质结构并改变乳腺癌细胞中关键基因表达的表观遗传变化。后一类基因的结构完整性通常是完好的，但其表达已因启动子区域的甲基化、与其启动子区域相互作用的组蛋白的去乙酰化或两种机制而发生了显著改变。受乳腺癌表观遗传变化影响的基因包括HoxA5、p21WAF、凝溶胶蛋白、BRCA1、BRCA2、E-钙黏蛋白、类固醇激素受体和视黄酸受体II。由于这些表观遗传修饰通常可通过某些药物治疗而逆转，它们代表了癌细胞中的薄弱环节，可被开发为新的预防和治疗策略的新型靶点。
