Establishing NIPBL as a Novel Biomarker in TNBC

Triple negative breast cancer (TNBC) is a subtype of breast cancer that is highly heterogeneous and extremely aggressive. It is characterised by lack of endocrine receptor expression for oestrogen and progesterone as well as HER2 expression, all major targetable biomarkers currently employed in therapies for other subtypes of breast cancer. TNBC patients have high relapse rates and dismal overall survival due to the lack of targets and the invasiveness of the cancer, which causes metastasis in the majority of cases. In this study, we reanalysed a 3D functional genomics screens from a previous study (Peck et al. 2021) conducted by the Translational Cancer Metabolism group. The screen assessed 200 of the most commonly altered genes in breast cancer. The study identified the histone acetyltransferase CREBBP as a targetable driver and novel tumour suppressor in TNBC as well as multiple other potential tumour suppressor genes. Here, we aimed to identify potential genes that only promoted growth when cells had a mutant TP53 status. Strikingly, the gene Nipped-B-like protein (NIPBL) was identified from our reanalysis to promote growth when silenced, however only when the cancer cells harboured TP53 mutations. We validated our findings using 3D spheroids that effectively recapitulate the unfavourable conditions found in vivo in aggressive tumour microenvironments, i.e. hypoxia and nutrient depletion. NIPBL is not currently known to directly interact with p53 or play a role in modulating cellular metabolism. Thus this study represents the first investigations into the interaction of these proteins in human cancers, with future work to validate this finding and ultimately confirm NIPBL as a bona fide tumour suppressor in aggressive cancers and a potential novel biomarker for targeted therapies in TNBC.