Stemness of Cancer: A Study of Triple-negative Breast Cancer From a Neuroscience Perspective.

Stemness, giving cancer cells massive plasticity enabling them to survive in dynamic (e.g. hypoxic) environments and become resistant to treatment, especially chemotherapy, is an important property of aggressive tumours. Here, we review some essentials of cancer stemness focusing on triple-negative breast cancer (TNBC), the most aggressive form of all breast cancers. TNBC cells express a range of genes and mechanisms associated with stemness, including the fundamental four "Yamanaka factors". Most of the evidence concerns the transcription factor / oncogene c-Myc and an interesting case is the expression of the neonatal splice variant of voltage-gated sodium channel subtype Nav1.5. On the whole, measures that reduce the stemness make cancer cells less aggressive, reducing their invasive/metastatic potential and increasing/restoring their chemosensitivity. Such measures include gene silencing techniques, epigenetic therapies as well as novel approaches like optogenetics aiming to modulate the plasma membrane voltage. Indeed, simply hyperpolarizing their membrane potential can make stem cells differentiate. Finally, we give an overview of the clinical aspects and exploitation of cancer/TNBC stemness, including diagnostics and therapeutics. In particular, personalised mRNA-based therapies and mechanistically meaningful combinations are promising and the emerging discipline of 'cancer neuroscience' is providing novel insights to both fundamental issues and clinical applications.