Mapping Bromodomains in breast cancer and association with clinical outcome

Javier Pérez-Pena,Atanasio Pandiella,Balázs Győrffy,Raquel Páez,Alberto Ocana,Verónica Corrales Sánchez,Cristina Nieto-Jiménez,Eva M Galan-Moya

doi:10.1038/s41598-019-41934-3

Abstract

A specific family of proteins that participate in epigenetic regulation is the bromodomain (BRD) family of proteins. In this work, we aimed to explore the expression of the BRD family at a transcriptomic level in breast cancer, and its association with patient survival. mRNA level data from normal breast and tumor tissues were extracted from public datasets. Gene set enrichment analysis (GSEA) was performed to identify relevant biological functions. The KM Plotter Online tool was used to evaluate the relationship between the presence of different genes and patient clinical outcome. mRNA level data from HER2+ breast cancer patients sensible and resistant to trastuzumab were also evaluated. The BRD family was an enriched function. In HER2 positive tumors the combined analyses of BRD2, BAZ1A, TRIM33 and ZMYND8 showed a detrimental relapse free survival (RFS). Similarly, the combined analysis of BRD2, BAZ1A, PHIP, TRIM33, KMT2A, ASH1L, PBRM1, correlated with an extremely poor overall survival (OS). The prognosis was confirmed using an independent dataset from TCGA. Finally, no relation between expression of BRD genes and response to trastuzumab was observed in the HER2 population. Upregulation of some BRD genes is associated with detrimental outcome in HER2 positive tumors, regardless trastuzumab treatment.

Highlights

Identification of oncogenic vulnerabilities with potential to be targeted therapeutically is a main goal in breast cancer[1,2]
We aimed to explore the expression of the BRD family of proteins in breast cancer and its association with patient survival
“FOXM1 pathway” was the function more upregulated, but components of this family have already been studied in breast cancer[16,17], so it was not the focus of our attention (Fig. 1A)

Summary

Introduction

Identification of oncogenic vulnerabilities with potential to be targeted therapeutically is a main goal in breast cancer[1,2]. Agents aiming to inhibit their function have been developed just recently, and they are currently in clinical evaluation at different stages, demonstrating a good toxicity profile[6,8]. They have shown activity in different solid tumors through the reduction of the expression of key TFs, including c-MYC or FOXM1, among others[9,10,11]. Molecular alterations like breast cancer, where combinations of agents can augment clinical efficacy, the identification of novel vulnerabilities with potential to be exploited therapeutically is a main objective[14,15]. In other tumor subtypes, some of the family members were amplified and linked with prognosis

Objectives

Methods

Results

Conclusion