Estrogen-Inducible LncRNA BNAT1 Functions as a Modulator for Estrogen Receptor Signaling in Endocrine-Resistant Breast Cancer Cells.

Abstract

Recent advances in RNA studies have revealed that functional long noncoding RNAs (lncRNAs) contribute to the biology of cancers. In breast cancer, estrogen receptor α (ERα) is an essential transcription factor that primarily promotes the growth of luminal-type cancer, although only a small number of lncRNAs are identified as direct ERα targets and modulators for ERα signaling. In this study, we performed RNA-sequencing for ER-positive breast cancer cells and identified a novel estrogen-inducible antisense RNA in the COL18A1 promoter region, named breast cancer natural antisense transcript 1 (BNAT1). In clinicopathological study, BNAT1 may have clinical relevance as a potential diagnostic factor for prognoses of ER-positive breast cancer patients based on an in situ hybridization study for breast cancer specimens. siRNA-mediated BNAT1 silencing significantly inhibited the in vitro and in vivo growth of tamoxifen-resistant ER-positive breast cancer cells. Notably, BNAT1 silencing repressed cell cycle progression whereas it promoted apoptosis. Microarray analysis revealed that BNAT1 silencing in estrogen-sensitive breast cancer cells repressed estrogen signaling. We showed that BNAT1 knockdown decreased ERα expression and repressed ERα transactivation. RNA immunoprecipitation showed that BNAT1 physically binds to ERα protein. In summary, BNAT1 would play a critical role in the biology of ER-positive breast cancer by modulating ERα-dependent transcription regulation. We consider that BNAT1 could be a potential molecular target for diagnostic and therapeutic options targeting luminal-type and endocrine-resistant breast cancer.