Targeting cancer stem cells Breast cancer is a major cause of cancer-related deaths among women. Anti-cancer strategies targeting cancer stem cells promise high specificity and fewer side effects. Health © Shutterstock Over the years, researchers have proposed the existence of cancer stem cells to explain carcinogenesis and disease relapse. As a result, cancer stem cells have emerged as a new target for eradicating and ultimately curing cancer. However, there is limited information available regarding the molecular differences between normal and cancer stem cells. In this context, the EU-funded MAMMASTEM (Molecular mechanisms of the regulation of mammary stem cell homeostasis and their subversion in cancer) project set out to investigate normal and cancer-causing mammary stem cells (MaSCs) by focusing on the role of the cell fate determinant Numb known for its role in neural development in Drosophila. Numb is a tumour suppressor in human breast cancer and its expression is lost in half of the cases. Numb controls two different pathways, namely p53 signalling and Notch, and its loss is associated with an overall poorer prognosis for breast cancer patients. Given that Numb is asymmetrically partitioned at the first division of normal MaSCs, MAMMASTEM researchers hypothesised that loss of Numb would affect the kinetics of division. To investigate and characterise the key molecular mechanisms governing normal MaSC biology, they used a technique that enabled them to isolate MaSCs with high purity. In addition, they followed a mouse genetics approach that allowed them to elucidate Numb as a central player in the regulation of MaSC asymmetric division. Cellular and biochemical analyses suggested that Numb is implicated in endocytosis and its correct localisation in endocytic vesicles might drive MaSC self-renewal. Furthermore, through a high-throughput siRNA-based screen, scientists discovered that the excessive degradation of Numb protein in breast cancer was due to E3 ligases. Targeting of these enzymes could restore Numb levels and inhibit tumour growth. Taken together, the MAMMASTEM work provided fundamental insight into the biological properties of normal and cancer MaSCs. In particular, targeting Numb dysfunction in breast cancer emerged as a valid strategy to eradicate cancer stem cells. Keywords Stem cells, breast cancer, Numb, p53, Notch, E3 ligase
