Amplification events with overexpression of know oncogenes have been demonstrated to participate in breast tumorigenesis. However, copy number gains are not positively correlated to transcriptional activation in many identified amplicons, which lack potential oncogenic drivers. Recently, Hsu et al. indicated that amplification of DNA regulatory elements, which are the binding sites of estrogen receptor, could induce transcriptional changes of distal targeting genes and drive breast tumorigenesis. In the published Cancer Cell paper, integrative analysis of three next-generation sequencing datasets (3C-seq, ERa ChIP-seq, and mate-pair seq) was conducted to mapping estrogen-induced chromatin interaction events associated with ERa-bound distant estrogen response elements (DERE) in breast cancer cells. Interestingly, DERE interaction sites clustered in two specific chromosomal regions- 17q23 and 20q13 that are frequently amplified in breast tumors. Prolonged exposure to estrogen or estrogenic compounds contributed to increase of DERE copies in either 17q23 or 20q13 regions, suggesting that DERE-involved amplification 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 ERa-positive breast cancers compared with ERa-negative breast cancers. Amplification of 17q23 and 20q13 were also specifically associated with reduced survival in ERa-positive breast cancers. Estrogen-induced DERE interactions repressed putative tumor suppressor gene expression and down-regulated gene networks associated with sensitivity to tamoxifen, pointing to a functional role of DERE amplification in ERa-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.
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