Amplification of Regulatory Elements Deregulates Target Genes

Genomic studies have identified multiple recurrent amplification events in breast cancer, some of which result in the overexpression of known oncogenes. However, gene copy number gains are not associated with transcriptional upregulation in many amplicons, and many lack obvious drivers. Hsu and colleagues hypothesized that amplification of DNA regulatory elements could induce transcriptional changes in distant target genes and drive tumorigenesis. Chromosome confirmation capture and estrogen receptor α (ERα) chromatin immunoprecipitation were coupled with DNA sequencing to identify estrogen-inducible long-range chromatin interaction events involving ERα-bound distant estrogen response elements (DERE) in breast cancer cells. Interestingly, DERE interaction sites clustered in specific chromosomal regions that are frequently amplified in breast cancer. Two such loci, 17q23 and 20q13, had the highest density of DEREs and number of interchromosomal interactions in the genome. Prolonged exposure to estrogen or estrogenic compounds promoted DERE aggregation and induced a significant number of amplification and fusion events involving either 17q23 or 20q13 in both breast cancer cell lines and breast stem/progenitor cells, suggesting that DERE-containing fusions and amplifications can arise due to sustained estrogen-induced physical contact between DEREs and target loci. Consistent with these findings, DERE copy numbers were significantly elevated in ERα-positive breast cancers compared with ERα-negative breast cancers. Amplification of 17q23 and 20q13 was also specifically associated with reduced survival in ERα-positive breast cancers. Estrogen-induced DERE interactions repressed putative tumor suppressor gene expression and downregulated gene networks associated with sensitivity to tamoxifen, pointing to a functional role of DERE amplification in ERα-positive breast cancer progression. In addition to providing insight into the consequences of recurrent amplifications in breast cancer, these findings raise the possibility that amplification of DNA regulatory elements may be a general mechanism of transcriptional deregulation during tumorigenesis.

Hsu PY, Hsu HK, Lan X, Juan L, Yan PS, Labanowska J, et al. Amplification of distant estrogen response elements deregulates target genes associated with tamoxifen resistance in breast cancer. Cancer Cell 2013;24:197–212.