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High mobility group A (HMGA) proteins are oncofoetal chromatin architectural factors that are widely involved in regulating gene expression. These proteins are unique, because they are highly expressed in embryonic and cancer cells, where they play a relevant role in cell proliferation, stemness, and the acquisition of aggressive tumour traits, i.e., motility, invasiveness, and metastatic properties. The HMGA protein expression levels and activities are controlled by a connected set of events at the transcriptional, post-transcriptional, and post-translational levels. In fact, microRNA (miRNA)-mediated RNA stability is the most-studied mechanism of HMGA protein expression modulation. In this review, we contribute to a comprehensive overview of HMGA-targeting miRNAs; we provide detailed information regarding HMGA gene structural organization and a comprehensive evaluation and description of HMGA-targeting miRNAs, while focusing on those that are widely involved in HMGA regulation; and, we aim to offer insights into HMGA-miRNA mutual cross-talk from a functional and cancer-related perspective, highlighting possible clinical implications.

Introduction: Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat because of its heterogeneity and lack of specific therapeutic targets. High Mobility Group A (HMGA) proteins are chromatin architectural factors that have multiple oncogenic functions in breast cancer, and they represent promising molecular therapeutic targets for this disease. Areas covered: We offer an overview of the strategies that have been exploited to counteract HMGA oncoprotein activities at the transcriptional and post-transcriptional levels. We also present the possibility of targeting cancer-associated factors that lie downstream of HMGA proteins and discuss the contribution of HMGA proteins to chemoresistance. Expert opinion: Different strategies have been exploited to counteract HMGA protein activities; these involve interfering with their nucleic acid binding properties and the blocking of HMGA expression. Some approaches have provided promising results. However, some unique characteristics of the HMGA proteins have not been exploited; these include their extensive protein-protein interaction network and their intrinsically disordered status that present the possibility that HMGA proteins could be involved in the formation of proteinaceous membrane-less organelles (PMLO) by liquid-liquid phase separation. These unexplored characteristics could open new pharmacological avenues to counteract the oncogenic contributions of HMGA proteins.