Abstract
The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.
Highlights
The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined
We identified commonly differentially expressed genes (106 up-; 379 downregulated in Breast cancer brain metastases (BCBM), Supplementary Data 6) enriched for pathways associated with the brain tumor microenvironment (GSEA; FDR < 0.25; normalized enrichment score (NES) ± 1.0), including GFAP, glial fibrillary acidic protein, gene targets of NR2E1 (TLX), nuclear receptor subfamily 2 group E member 1(encoded protein regulates adult neural stem cell proliferation), and PTPRC, protein tyrosine phosphatase receptor C (Fig. 2b and Supplementary Data 7)
Our data shows features of luminal BCBM leading to a complete remodeling of the BCBM transcriptomic and mutational landscape characterized by widespread alterations of homologous recombination deficiency (HRD) pathways
Summary
The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Breast cancer cells exhibit exceptional plasticity, capable of adapting to sequential bouts of therapeutic pressure, as well as the vastly changing microenvironmental landscape These adaptations can be immediate or delayed, often depending on whether tumors are ER-positive or ER-negative[2]. Acquired driver genomic alterations in BCBM predominantly consist of the HER, PI3K, and cyclin-dependent kinase (CDK) pathways; many of which are enriched compared to the primary tumor[12,13,14]. This general strategy has classified potentially clinically informative adaptations, only a handful of studies have investigated these mutations in experimental models or in patients, especially in the context of all breast tumor subtypes. DNA repair pathway defects, including homologous recombination deficiency (HRD), are extensively profiled and functionally validated in luminal BCBMs
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