Luminal breast cancer remains a major clinical challenge with over 2 million cases diagnosed annually. While prognosis is favourable in these patients, roughly 40% will relapse over the course of the next 20 years. Understanding the evolution of disseminated tumour cells at distal sites is critical to effectively treating these patients. While metastatic driver mutations, such as those in the Oestrogen Receptor (ESR1) gene, can be identified in many cases for a significant proportion of patients, clear drivers remain elusive. A limitation of previous genomics studies in metastatic breast cancer is their focus on the coding genome. Advances in our understanding have revealed the critical role of regulatory elements such as enhancers and promoters in transcriptional regulation. This effect is mediated through the functional and hierarchical organisation of chromatin within the nucleus, the key unit of chromatin organisation is the Topologically Associating Domains (TADs). TAD organisation is, in part, mediated by the CCCTC-Binding Factor (CTCF) protein which physically binds to DNA mediating the formation of loops and domains. Together promoters, enhancers, and CTCF-bound regions provide potential as sites for non-coding mutations to occur, drastically impacting gene regulation and tumour evolution. In this work we interrogate the contribution of regulatory element mutations in the evolution of metastatic breast cancer. This is done through two projects. First, a proof of principle study functionally characterising a clinically relevant CTCF binding site mutation. Second, through the design of an informed panel of regulatory regions utilised in a longitudinal targeted sequencing study in patient samples and a CRISPRi perturbation study in cell lines. Through these studies we provide evidence that the mutation of TAD boundary associated CTCF binding sites is unlikely to contribute to tumour evolution. We also fail to identify recurrence of non-coding drivers, though more patient specific mutations may contribute to metastatic evolution. Results obtained from the CRISPRi screen illustrate the functionality of the regulatory regions in the panel, identifying regulatory elements that confer fitness or vulnerabilities when specifically repressed. This study identifies that repression of several members of the NF-κB signalling pathway provides MCF7 cells with an advantage in adapting to oestrogen deprivation. This data underlines the importance of regulatory regions in the evolution of luminal breast cancers and indicates that non-genetic mechanisms may play a key role.