THE ROLE OF NUMB IN STEM CELL HOMEOSTASIS AND BREAST TUMORIGENESIS

In this thesis I report my investigations on the role of Numb, a known cell fate determinant in regulating Stem Cell homeostasis and in the pathogenesis of human and mouse breast cancer. I have investigated the characterization of the biological and molecular features of Numb KO murine breast model in comparison with Numb deficient human breast cells model. I exploited an in vitro system (the mammosphere assay) to propagate and enrich breast SCs, in combination with a cell membrane labeling system (PKH-assay) to purify SCs. The absence of Numb in both murine and human models helped to clarify the role of this “fate determinant” starting from the SC first mitotic division in vitro up to the in vivo tumorigenesis and related Numb reconstitution consequences. Through the comparison of the self-renewal properties of normal and cancer SCs, both in terms of proliferative cell fate and Numb partitioning, and the study of the molecular mechanisms underlying abnormal growth properties, functional attenuation and pharmacological restoration of signaling pathways in mammary CSCs, I have attempted to answer the open questions regarding the role of SCs in cancer development and maintenance, focusing the attention on a first possible direct evidence for cancer SC targeted therapy.