Department of Molecular Medicine/Institute of Biotechnology, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Cancer Cell. 2013 Aug 12;24(2):197-212. doi: 10.1016/j.ccr.2013.07.007.
A causal role of gene amplification in tumorigenesis is well known, whereas amplification of DNA regulatory elements as an oncogenic driver remains unclear. In this study, we integrated next-generation sequencing approaches to map distant estrogen response elements (DEREs) that remotely control the transcription of target genes through chromatin proximity. Two densely mapped DERE regions located on chromosomes 17q23 and 20q13 were frequently amplified in estrogen receptor-α-positive luminal breast cancer. These aberrantly amplified DEREs deregulated target gene expression potentially linked to cancer development and tamoxifen resistance. Progressive accumulation of DERE copies was observed in normal breast progenitor cells chronically exposed to estrogenic chemicals. These findings may extend to other DNA regulatory elements, the amplification of which can profoundly alter target transcriptome during tumorigenesis.
基因扩增在肿瘤发生中的因果作用是众所周知的，而 DNA 调控元件的扩增作为致癌驱动因素尚不清楚。在这项研究中，我们整合了下一代测序方法来绘制远程雌激素反应元件 (DEREs)，这些元件通过染色质接近远程控制靶基因的转录。两个位于染色体 17q23 和 20q13 上的密集映射的 DERE 区域在雌激素受体-α阳性腔乳腺癌中经常扩增。这些异常扩增的 DERE 使靶基因表达失控，可能与癌症发展和他莫昔芬耐药有关。在长期暴露于雌激素类化学物质的正常乳腺祖细胞中观察到 DERE 拷贝的逐渐积累。这些发现可能扩展到其他 DNA 调控元件，其扩增在肿瘤发生过程中会极大地改变靶转录组。
