Nuclear Receptor Coactivator 2 Promotes Human Breast Cancer Cell Growth by Positively Regulating the MAPK/ERK Pathway.

Mengjiao Cai,Lingzhi Wu,Suxi Gu,Huan Chen,Xin Liang,Suxia Han,Yiping Dong,Xiao Sun

doi:10.3389/fonc.2019.00164

Abstract

As a member of the p160 steroid receptor coactivator (SRC) family, nuclear receptor coactivator 2 (NCOA2) is known to play essential roles in many physiological and pathological processes, including development, endocrine regulation, and tumorigenesis. However, the biological function of NCOA2 in breast cancer is not fully understood. We found that the copy number of the NCOA2 gene was frequently amplified in four breast cancers datasets, varying from 6 to 10%, and the mRNA levels of NCOA2 were also upregulated in 11% of the sequenced cases/patients (TCGA provisional dataset). Next, we confirmed that NCOA2 silencing significantly suppressed cell proliferation in different breast cancer cell lines, by inducing cell cycle arrest and apoptosis. Mechanistically, whole-transcriptome sequencing (RNA-Seq) analysis showed that NCOA2 depletion leads to downregulation of the MAPK/ERK signaling cascade, possibly via downregulating NCOA2's downstream target RASEF. In conclusion, our results suggest NCOA2 as a potential target of therapeutics against breast cancer.

Highlights

Nuclear receptor coactivator 2 (NCOA2), known as steroid receptor coactivator 2 (SRC-2), belongs to the p160 steroid receptor coactivator (SRC) family
The copy number of the NCOA2 gene was analyzed by using the cBioPortal online tool and found to be frequently amplified in four independent breast cancers datasets [METABRIC, Nat Commun 2016; BRCA, INSERM 2016; TCGA Pancancer Atlas; The Metastatic Breast Cancer (MBC) Project] [27,28,29], varying from 5 to 14% amplification (Figure 1A)
By cross-comparing the results obtained from the Ramaswamy Multi-cancer Statistics using the online Oncomine tool, we found that the expression of NCOA2 in breast cancer was relatively higher than that in other cancer types, including prostate cancer, bladder cancer, lung cancer, and lymphoma among others (Figure 1C) [30], suggesting an important role for NCOA2 in regulating breast cancer development

Summary

Introduction

Nuclear receptor coactivator 2 (NCOA2), known as steroid receptor coactivator 2 (SRC-2), belongs to the p160 steroid receptor coactivator (SRC) family This protein family contains three members, NCOA1, NCOA2, and NCOA3 [1,2,3], which are recruited to the enhancer/promoter regions of target genes and serve as transcriptional coactivators for ligand-bound nuclear receptors and transcription factors [4]. SRC proteins contain three types of domains: [1] The N-terminal basic helix-loop-helix-Per/ARNT/Sim (bHLH-PAS) domain, which interacts with transcription factors [5, 6]; [2] The LXXLL (L for leucine and X for any amino acid) motif, in the central region, responsible for nuclear hormone receptors (NRs) binding [7, 8]; [3] Two distinct transcriptional activation domains (AD1 and AD2), at the C-terminus, needed for recruiting additional coregulators, such as histone acetyltransferases (HAT), coactivator-associated arginine methyltransferase 1 (CARM1) and protein arginine methyltransferases (PRMTs) [9,10,11,12]. NCOA2 is amplified or overexpressed in 8% of the primary pancreatic cancers, and its expression level is associated with tumor relapse following androgen deprivation therapy (ADT); mechanistically, NCOA2 overexpression in prostate tumors may lead to hyperactivation of the PI3K/AKT signaling, exacerbating tumor malignance [20]

Methods

Results

Conclusion