Abstract
70-75% breast cancer patients are estrogen receptor alpha positive (ERα+), and the antiestrogen drug tamoxifen has been used for the past three decades. However, in 20-30% of these patients, tamoxifen therapy fails due to intrinsic or acquired resistance. A previous study has showed ERα signaling still exerts significant roles in the development of tamoxifen resistance and several lncRNAs have been demonstrated important roles in tamoxifen resistance. But ERα directly regulated and tamoxifen resistance related lncRNAs remain to be discovered. We reanalyze the published ERα chromatin immunoprecipitation-seq (ChIP-seq) and RNA-seq data of tamoxifen-sensitive (MCF-7/WT) and tamoxifen-resistant (MCF-7/TamR) breast cancer cells. We demonstrate that there are differential ERα recruitment events and the differentials may alert the expression profile in MCF-7/WT and MCF-7/TamR cells. Furthermore, we make an overlap of the ERα binding lncRNAs and differentially expressed lncRNAs and get 49 ERα positively regulated lncRNAs. Among these lncRNAs, the expression levels of AC117383.1, AC144450.1, RP11-15H20.6, and ATXN1-AS1 are negatively correlated with the survival probability of breast cancer patients and ELOVL2-AS1, PCOLCE-AS1, ITGA9-AS1, and FLNB-AS1 are positively correlated. These lncRNAs may be potential diagnosis or prognosis markers of tamoxifen resistance.
Highlights
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among female cancers, with an estimated 2.1 million newly diagnosed female breast cancer cases in 2018 around the world [1]
The ERα directly regulated genes in MCF-7/TamR-E2 cells just had 25.0% overlap of MCF-7/TamR cells (Figures 3(a) and 3(b)), which indicated that ERα signaling in MCF-7/TamR cells was E2-dependent
Gene Ontology (GO) enrichment analysis of ERα binding events showed that the misregulated autophagy and I-kB kinase/NF-kB signaling pathway in MCF-7/TamR cells may lead to tamoxifen resistance (Figures 3(c) and 3(d))
Summary
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among female cancers, with an estimated 2.1 million newly diagnosed female breast cancer cases in 2018 around the world [1]. Noncoding RNAs (ncRNAs) play an important role in tamoxifen resistance [5]. Urothelial carcinoma associated 1 (UCA1) has been confirmed to contribute to multiple cancer drug resistance, including cisplatin resistance in bladder cancer and ovary cancer, gefitinib resistance in lung cancer, and tamoxifen resistance in breast cancer [7]. Breast cancer antiestrogen resistance 4 (BCAR4), lncRNA-ROR (ROR, regulator of reprogramming), colon cancer associated transcript 2 (CCAT2), DSCAM-AS1, and LINC00894 are reported to enhance or attenuate tamoxifen resistance [8]. The important role and complex working mechanism of BioMed Research International lncRNAs in tamoxifen resistance still need to be illustrated, and there is an urgent need to discover more novel diagnosis and prognosis markers
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