A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation

Abstract

Estrogen receptor-α (ER)-positive breast cancer cells undergo hormone-independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance. Up-regulation of the ER gene (ESR1) is critical for this process, but the underlying mechanisms remain unclear. Here we show that the combination of transcriptome and fluorescence in situ hybridization analyses revealed that oestrogen deprivation induced a cluster of noncoding RNAs that defined a large chromatin domain containing the ESR1 locus. We termed these RNAs as Eleanors (ESR1 locus enhancing and activating noncoding RNAs). Eleanors were present in ER-positive breast cancer tissues and localized at the transcriptionally active ESR1 locus to form RNA foci. Depletion of one Eleanor, upstream (u)-Eleanor, impaired cell growth and transcription of intragenic Eleanors and ESR1 mRNA, indicating that Eleanors cis-activate the ESR1 gene. Eleanor-mediated gene activation represents a new type of locus control mechanism and plays an essential role in the adaptation of breast cancer cells.

Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

“…The long intergenic non-coding RNA-ROR has been shown to induce epithelial-to-mesenchymal transition and contribute to breast cancer metastasis (44) and to enhance ERα signaling, conferring resistance to tamoxifen (45). A recent study also indicated that a cluster of lncRNAs, termed Eleanors (ESR1 locus enhancing and activating noncoding RNAs) located within the genomic region containing the ESR1 gene can regulate ERα levels through an enhancer function (46). Of note is the fact that the lncRNA SRA1 (steroid receptor RNA activator 1) acted as a coactivator of ERα, and this action depended on the phosphorylation of ERα at Ser118 (47).…”

Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate

“…These functional studies provide strong evidence for the potential clinical relevance of ESR1 amplification as a mechanism of ERα pathway regulation. One additional study used LTED MCF7 cells to show a change of ESR1 gene status detectable by FISH; however, the FISH signals were RNase-sensitive and no ESR1 copy number increase was detectable by ESR1 qPCR, suggesting that the FISH results may have been due to probe hybridization to abundant RNA [103] . Gene amplifications in human cancers are markers of the tumor's dependence on the encoded protein, and point to a potential target of therapy [18,20,21,[45][46][47]104,105] .…”

Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer

“…Another example includes GAS5 lncRNA, a cell cycle regulator, which is down regulated in breast cancer samples [29]. Some of the candidate lncRNAs that are shown to be aberrantly expressed in breast cancer include H19 [26, 30], aHIF [31], BCYRN1 [32], UCA1 [33], SRA RNA [34], ZFAS1 [35], CCAT2 [36], LSINCT5 [37], NKILA [25], treRNA [20], Eleanors [38] and MALAT1 [39–42]. Recent bioinformatics studies have identified several novel lncRNAs, the expression of which is altered in breast cancer patients: some of these have the potential to be used as prognostic markers [43–45].…”