Widespread association of ERα with RMRP and tRNA genes in MCF-7 cells and breast cancers

tRNA gene transcription by RNA polymerase III (Pol III) is a tightly regulated process, but dysregulated Pol III transcription is widely observed in cancers. Approximately 75% of all breast cancers are positive for expression of Estrogen Receptor alpha (ER alpha), which acts as a key driver of disease. MCF-7 cells rapidly upregulate tRNA gene transcription in response to estrogen and ChIP-PCR demonstrated ER alpha enrichment at tRNA(Leu) and 5S rRNA genes in this breast cancer cell line. While these data implicate the ER alpha as a Pol III transcriptional regulator, how widespread this regulation is across the 631 tRNA genes has yet to be revealed. Through analyses of ER alpha ChIP-seq datasets, we show that ER alpha interacts with hundreds of tRNA genes, not only in MCF-7 cells, but also in primary human breast tumours and distant metastases. The extent of ER alpha association with tRNA genes varies between breast cancer cell lines and does not correlate with levels of ER alpha binding to its canonical target gene GREBI. Amongst other Pol III-transcribed genes, ER alpha is consistently enriched at the long non-coding RNA gene RMRP, a positive regulator of cell cycle progression that is subject to focal amplification in tumours. Another Pol III template targeted by ER alpha is the RN7SL1 gene, which is strongly implicated in breast cancer pathology by inducing inflammatory responses in tumours. Our data indicate that Pol III-transcribed non-coding genes should be added to the list of ER alpha targets in breast cancer.

Automated summary

Transcription of tRNA genes is tightly regulated by RNA polymerase III (Pol III), but dysregulated Pol III transcription is widely observed in cancers, with ER alpha acting as a key driver in breast cancer. ER alpha interacts with hundreds of tRNA genes, not only in MCF-7 cells, but also in primary human breast tumours and distant metastases.