Identification of Molecular Mediators of Endocrine Resistant and Brain Metastatic Breast Cancer Through Analysis of Omics Data.

Breast cancer metastases is one of the leading causes of cancer related death in women worldwide. Our fundamental understanding of treatment resistance, disease progression and metastasis in cancer has greatly improved with the advent of -omic technologies. However, a deeper understanding of the molecular complexity, in particular, in the context of brain metastasis is still lacking. In this thesis, through interrogation of high through-put transcriptomic, genomic and other data, clinically relevant molecular mediators of endocrine resistant and brain metastatic breast cancer are identified.Estrogen receptor positive (ER+) cancer accounts for ≈70% of all breast cancer cases, with endocrine resistance a major clinical problem. In results Chapter 2, elucidation of the role p160 proteins, SRC-1 and AIB1, play in endocrine resistance is given. Specifically, a previously under appreciated novel role for Nucleosome Remodeling and Deacetylase (NuRD) complex mediated gene repression is demonstrated, along with identification of PARP1 as common to p160 interactomes in endocrine resistant cells. Moreover, data here, underscores the necessity to better understand the role of epigenetic aberrations in breast cancer metastases, in particular in the context of treatment resistance and clinically relevant receptor discordance.In Chapter 3 and 4, along with intrinsic molecular subtype switching observed in brain metastases, most prominent in ER+ patients; an unprecedented subtype specific analysis of molecular alterations in brain metastatic breast cancer is provided, where collectively, this study will serve as a critical reference for future transcriptomic studies of brain metastases. Lastly, in Chapter 4, DNA repair deficiency is found to be enriched in brain metastatic disease. Compelling pre-clinical data indicates homologous recombination deficiency (HRD) specifically may be a key therapeutic vulnerability to exploit for treatment of breast cancer brain metastases, and should inform future clinical studies.In conclusion, work presented here comprehensively characterises novel molecular mediators of endocrine resistant and brain metastatic breast cancer with potential therapeutic implications for treatment.</p

Transcriptome characterization of matched primary breast and brain metastatic tumors to detect novel actionable targets.

Background: Breast cancer brain metastases (BrMs) are defined by complex adaptations to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly understood, as does their potential for clinical targeting. We utilized genome-wide molecular profiling to identify therapeutic targets acquired in metastatic disease.Methods: Gene expression profiling of 21 patient-matched primary breast tumors and their associated brain metastases was performed by TrueSeq RNA-sequencing to determine clinically actionable BrM target genes. Identified targets were functionally validated using small molecule inhibitors in a cohort of resected BrM ex vivo explants (n = 4) and in a patient-derived xenograft (PDX) model of BrM. All statistical tests were two-sided.Results: Considerable shifts in breast cancer cell-specific gene expression profiles were observed (1314 genes upregulated in BrM; 1702 genes downregulated in BrM; DESeq; fold change > 1.5, Padj Conclusions: RNA-seq profiling of longitudinally collected specimens uncovered recurrent gene expression acquisitions in metastatic tumors, distinct from matched primary tumors. Critically, we identify aberrations in key oncogenic pathways and provide functional evidence for their suitability as therapeutic targets. Altogether, this study establishes recurrent, acquired vulnerabilities in BrM that warrant immediate clinical investigation and suggests paired specimen expression profiling as a compelling and underutilized strategy to identify targetable dependencies in advanced cancers.</p