Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance

Abstract

Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let‐7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF‐7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF‐7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer‐regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

<p>Construction and Analysis of a Long Non-Coding RNA-Associated Competing Endogenous RNA Network Identified Potential Prognostic Biomarkers in Luminal Breast Cancer</p>

“…However, these markers focused on TNBC or distant metastasis. [6][7][8][10][11][12][13] Recent studies have revealed that lncRNAs played vital roles in the development of cancers. 21,22 Further, germline mutations can also predict tumor recurrence in breast cancer patients.…”

“…Therefore, the identification of prognostic markers, which can be potential targets, is of importance. Recently, genes or proteins were proved to be an oncogene role or promoting metastasis in the luminal subtype, [10][11][12][13] while little were verified to be related to overall survival (OS). Moreover, most of them were genomic, along with some microRNAs (miRNA), while Long non-coding RNAs (lncRNA) were rarely mentioned.…”

“…21 In addition, prognostic roles and relationship with tamoxifen resistance were also mentioned. 13,22 Recently, competitive endogenous RNA (ceRNA), as a whole view of transcription, has gradually become a useful tool for identifying prognostic lncRNAs. The ceRNA hypothesis suggests that lncRNAs can competitively bind to miRNAs, thereby preventing their binding to mRNA, and consequently regulating mRNA expression.…”

The emerging role of BET inhibitors in breast cancer

“…JQ1 attenuated proliferation of tamoxifen-resistant ER + cells at a greater extent comparing to parental cells, by reducing BRD3/4 recruitment to ERa promoter [ 32 ]. In addition to this, ENST00000456526 is a long noncoding RNA, namely LOL (lncRNA of luminal), which is overexpressed in luminal breast cancer [ 65 ]. ER + tamoxifen-resistant cells demonstrate a higher LOL expression compared to parental cells.…”

<p>Long Non-Coding RNAs in Drug Resistance of Breast Cancer</p>

“…Knockdown of LOL reverses TAM resistance in TamR MCF-7 cells by sponging let-7 miRNAs. 82 LncRNA DSCAM-AS1 promotes TAM resistance via the miR-137/EPS8 axis or by modulating GREB1, a target of ER. It promotes cell reproduction and suppresses cell apoptosis by acting as a ceRNA of miR-137 and increasing EPS8 expression.…”