Abstract P2-05-03: Whole genome transcriptome analysis of sequential breast to brain metastasis uncovers new signalling pathways and druggable targets

Abstract

Abstract The occurrence of brain metastasis (BM) in breast cancer (BC) is currently on the rise across all molecular subtypes with 10-30% reported incidence. The need to uncover the mechanisms underlying this clinically devastating complication is apparent, and in the current study we sought to identify BC cell mediators of BM. In our cohort of metastatic patients (n=196) we found that BM developed in 13% of the cases. Despite the previous reports of negative ER status being a risk factor for BM, the ER+ve patients accounted for 42% of all diagnosed BM. To elucidate the gene alterations required for successful colonisation of the brain we undertook RNA sequencing (RNA-seq) of sequential breast to brain metastasis of known receptor status (n=7).This study presents the first whole transcriptome next-generation RNA-seq analysis of resected BM and their matching primary breast tumours. We identified 500 differentially expressed genes (DEGs) (< 0.05, fcThreshold >±1.5), accounting for those that were both upregulated and downregulated in BM compared to the primary. Analysis of protein-coding genes identified collective ER-specific metastatic pathways. Additionally, common functional pathways altered included ECM, cell adhesion and neuronal differentiation. Our analysis of the BM transcriptomic landscape and verification in cell line models that preferentially metastasise to the brain has unravelled a complex network of driver genes, cooperating with stromal derived factors, responsible for the organ-specific behaviour of the metastatic cells. Genes such as ANTRX1, THBS2, FAP, VCAN and TIMP2 were found to be part of the invasion and migration network that drives the extravasation of the BM cells. Furthermore, an EMT stemness signalling network driven by ANTRX1and WNT pathway driven RUNX was prominent in the cells acquiring the ability to migrate to the brain. Additional work is being carried out on uncovering the adaptations that re-activate the dormant brain metastatic cells and the contribution of the neuronal niche in the facilitating the colonisation by the MBC. This study highlights the requirement of unique gene sets for the invasion, migration and colonisation to the brain and that functional characterisation of the DEGs will enable the identification of novel molecular targets for prevention and treatment of breast cancer BM. Citation Format: Varešlija D, Fagan A, Buckley P, Farrell M, Hill A, Young L. Whole genome transcriptome analysis of sequential breast to brain metastasis uncovers new signalling pathways and druggable targets. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-03.