Endocrine resistance in ER-positive breast cancers is a common occurrence with hormonal therapies leading to accelerated tumour progression and metastatic complications. The exact molecular mechanisms driving resistance are still unclear and need further elucidation. In this study, long noncoding RNAs were highlighted as key players in orchestrating the complicity of different molecular pathways of resistance. LncRNAs are pervasively transcribed across the genome, measuring > 200 nucleotides in length, and found to be dysregulated in several tumorigenic pathways.
We hypothesised that tamoxifen resistance is influenced by dysregulated lncRNAs, and they constitute novel targets for nominating new biomarkers and therapeutics. To first investigate this, we generated a list of lncRNAs differentially expressed between tamoxifen resistant and sensitive MCF-7 cells using RNA sequencing. Of which, LUCAT1, SOX21-AS1, NR2F1-AS1, and HOTAIRM1 were selected to undergo further molecular validation studies, mainly siRNA mediated depletion of expression in tamoxifen resistant cells, then assessing tamoxifen sensitivity in vitro. While the 4 nominated lncRNAs’ expression was significantly high in tamoxifen resistant MCF-7 compared to tamoxifen sensitive MCF-7, no observable change in the tamoxifen sensitivity was observed when silencing any of the lncRNAs. To aid further candidate lncRNAs selection for invitro studies, GEO and TCGA databases were searched for data related to tamoxifen resistant phenotype, analyzing the data allowed for expanding our understanding of the genotypic changes related to tamoxifen resistance, as many genes known in the pathway of resistance were confirmed. Also, this offers grounds for nominating promising candidate lncRNAs in the pathway of tamoxifen resistance. In conclusion, RNA-seq analysis identified many dysregulated lncRNAs and protein coding genes, of which LUCAT1, NR2F1- AS1, SOX21-AS1 and HOTAIRM1 were prioritized as lncRNAs driving tamoxifen resistance in breast cancer. LUCAT1 was promising after bioinformatics investigation and remains a significant candidate for invitro validation. It was showed that comparisons, relating and overlapping between differentially expressed genes from RNA-seq and publicly available datasets resulted in nominating lncRNA ZNRD1ASP as possible candidate, additional in-depth analysis is needed.
