Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer

Wan-Xin Peng,Pratirodh Koirala,Liu Yang,Jiahong Jiang,Yin-Yuan Mo,Huaixiang Zhou,Ziqiang Zhang

doi:10.1038/s41419-021-04288-1

Abstract

Selective estrogen receptor modulators (SERMs) such as tamoxifen have proven to be effective in the treatment of estrogen receptor (ER) positive breast cancer. However, a major obstacle for such endocrine therapy is estrogen independent growth, leading to resistance, and the underlying mechanism is not fully understood. The purpose of this study was to determine whether long non-coding RNAs (lncRNAs) are involved in regulation of estrogen independent growth and tamoxifen resistance in ER positive breast cancer. Using a CRISPR/Cas9-based SAM (synergistic activation mediator) library against a focus group of lncRNAs, we identify Lnc-DC as a candidate lncRNA. Further analysis suggests that Lnc-DC is able to reduce tamoxifen-induced apoptosis by upregulation of anti-apoptotic genes such as Bcl2 and Bcl-xL. Furthermore, Lnc-DC activates STAT3 by phosphorylation (pSTAT3Y705), and the activated STAT3 subsequently induces expression of cytokines which in turn activate STAT3, forming an autocrine loop. Clinically, upregulation of Lnc-DC is associated with poor prognosis. In particular, analysis of a tamoxifen-treated patient cohort indicates that Lnc-DC expression can predict the response to tamoxifen. Together, this study demonstrates a previously uncharacterized function of Lnc-DC/STAT3/cytokine axis in estrogen independent growth and tamoxifen resistance, and Lnc-DC may serve as a potential predictor for tamoxifen response.

Highlights

Estrogen plays a critical role in breast cancer development because estrogen can stimulate cancer cell growth through estrogen receptor (ER)
The present study demonstrates Lnc-DC as a potential long non-coding RNAs (lncRNAs) involved in estrogen independent growth and tamoxifen resistance
Dysregulation of Lnc-DC may contribute to the clinical endocrine therapy resistance, and Lnc-DC may serve as a biomarker to predict the response to tamoxifen

Summary

Introduction

Estrogen plays a critical role in breast cancer development because estrogen can stimulate cancer cell growth through estrogen receptor (ER). A number of lncRNAs have been implicated in cancer initiation, progression, and metastasis as well as stem cell maintenance [10,11,12,13,14,15]. This may have to do with their ability to interact with DNA, RNA, or protein to regulate gene expression through which lncRNAs may serve as (1) signals for transcription; (2) decoys to titrate transcription factors; (3) guides for chromatinmodifying enzymes to be recruited to target genes, and (4) scaffolds to bring together multiple proteins to form functional ribonucleoprotein complexes [16,17,18,19]. Our goal of this study was to explore whether lncRNAs can regulate genes involved in estrogen independent growth and tamoxifen resistance

Objectives

Methods

Findings

Conclusion