LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer

Abstract

Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although lncRNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR is up-regulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the lncRNA HOTAIR is directly repressed by ER and its up-regulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…The authors concluded that HOTAIR increases ligandindependent ERα transcription. This observation is concordant with a report of increased HOTAIR immunstaining in tamoxifen-resistant human breast tumors (Xue et al 2016b). …”

“…HOTAIR is upregulated by HIF-1α, histone methylase MLL1, and coactivator p300 (Bhan, et al 2017). HOTAIR was reported to be induced by E 2 in MCF-7 BCa cells (Bhan, et al 2013), but others reported that E 2 -ERα directly that repressed HOTAIR in MCF-7 cells by binding to a genomic site 14.5 kB upstream of HOTAIR (Xue, et al 2016b). HOTAIR is downregulated by miR-141 (Chiyomaru, et al 2014) and is directly targeted by miR-34a in PCa cells (Chiyomaru, et al 2013).…”

“…ERα interacts directly of HOTAIR in RNA pulldown assays using nuclear extracts from MCF-7 BCa cells (Xue, et al 2017). Overexpression of HOTAIR in MCF-7 cells grown under hormone-free (serum-starved) medium conditions increases the number of DNA sites to which ERα binds in chromatin immunoprecipitation assays (ChIP) and increases mRNA expression of some ERα target genes, e.g., GREB1, TFF1, PGR, and CTSD (Xue et al 2016b). The authors concluded that HOTAIR increases ligandindependent ERα transcription.…”

Noncoding RNAs in breast cancer

“…Therefore, loss of BRCA1 or upregulation of HOTAIR results in the reprogramming of the genome-wide PRC2-binding pattern in breast epithelial cells, leading to the altered methylation signature found in aggressive breast cancer cells [178]. Recently HOTAIR has been shown to be upregulated in tamoxifen-resistant breast cancer tissues compared with their primary counterparts [179]. This facilitates the ligand-independent activation of ER, which contributes to tamoxifen resistance [179].…”

Genome-wide analysis of long non-coding RNA expression and function in colorectal cancer

“…6 In recent years, several studies have implicated lncRNAs in various malignancies. For instance, HOTAIR has been reported as being overexpressed in breast cancer and 7,8 CRC. [9][10][11] CCAT2 was identified as a novel lncRNA overexpressed in CRC which promotes metastasis and chromosomal instability.…”