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.
Highlights
Estrogen receptor-a (ER)-positive breast cancer cells undergo hormone-independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance
We found that up-regulation of ESR1 was important for LTED cell adaptation, which was maintained by novel ncRNAs produced from a large chromatin domain of the ESR1 gene
We found a novel type of ncRNA-mediated gene locus control in breast cancer adaptation
Summary
Estrogen receptor-a (ER)-positive breast cancer cells undergo hormone-independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance. 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. ER functions as a nuclear receptor-type transcription factor upon binding to oestrogen and regulates the expression of various target genes. Endocrine therapies, such as the use of an aromatase inhibitor (AI) that blocks oestrogen production, are the most effective for ER-positive breast cancers[2]. The potential roles of lncRNAs in cancer cell adaptation are unknown
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