Abstract P3-05-10: Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells

Abstract

Abstract Endocrine therapies that blocks estrogen production are effective for estrogen receptor (ER)-positive breast cancer. However, endocrine therapy treated patients eventually experience relapse after a long period of estrogen deprivation. The mechanism underlying acquisition of estrogen independent growth by ER positive breast cancer cells remains unclear. To understand such molecular mechanism, we used a cell model LTED (long term estrogen deprivation) which MCF7 cells were cultured under estrogen deprivation for 4-10 months. In LTED cells, we found that ER encoded gene ESR1 was up-regulated and ER overproduction was essential for estrogen-independent cell growth. We also revealed that RNA transcriptions of the ESR1 and several neighbor genes were co-induced from both coding and non-coding regions in LTED cells, using RNA-sequence. These highly transcribed regions were corresponded to active histone modifications and transcription factor bindings according to publically available genome-wide analyses data. Fluorescence in situ hybridization (FISH) analyses indicated that RNA from the chromatin domain region nearby ESR1 were co-localized and made foci in nucleus. We found non-coding regions that are particularly highly transcribed. FISH analyses indicated that RNAs from these regions might interact with the parental ESR1 gene locus. Recent studies have shown that non-coding RNAs are involved in transcriptional regulation and chromatin regulation. To understand the role of the non-coding RNA, we have generated MCF7 cells lines that lack the non-coding site, using CRISPR/CAS9 system. We found that mRNA transcription of multiple genes including ESR1 were impaired by the deletion. These findings suggested that these non-coding RNAs may be involved in chromatin regulation of the chromatin domain nearby ESR1. In this study, we found non-coding RNAs that control transcription of chromatin domain genes in ER positive breast cancer cells. Such non-coding RNA mediated transcriptional regulation might be critical for endocrine therapy resistance adaptation. Citation Format: Fujiwara S, Saitoh N, Tomita S, Abdalla MO, Iwase H, Nakao M. Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-10.