Simone Sabbioni

he tumor suppressor protein, Numb, safeguards against the emergence and the expansion of cancer stem cells (CSCs). Indeed, Numb loss occurs in ~30% of human breast cancers (BC) and correlates with biological aggressiveness and poor prognosis. A well-established mechanism responsible for Numb loss in BC is its aberrant proteasomal degradation. Thus, the identification of the proteasomal machinery responsible for Numb loss would not only provide clues as to the underlying lesions in Numb-deficient cancers, but could pave the way to the development of novel strategies to restore Numb expression and curbs tumorigenic potential of Numb-deficient BCs through the selective targeting of CSCs ensues.

Through a siRNA-based high-throughput screening in Numb-deficient MDA-MB-361 cells, RBX1 and FBXW8, both components of the Cullin-RING E3-ligase complexes (CRLs), were identified as negative regulators of Numb stability in Numb-deficient cells.
By comparing the Numb-deficient with the Numb-proficient (MDA-MB-231) BC cell models, we studied, through a combination of in vitro and in vivo pharmacological and genetic approaches, the effects on Numb expression levels and tumor phenotypes achieved upon the impairment of RBX1/FBXW8-CRL function.

Overall, we formally demonstrated the involvement of a CRL complex in the excessive degradation of Numb in Numb-deficient BCs. Interestingly, pre-clinical in vivo models also provided proof-of- principle of the selective therapeutic value of targeting RBX1 and FBXW8 CRL components in these tumors. Moreover, our results supported the notion that the proteasome-inhibitor Bortezomib and the CRL-inhibitor Pevonedistat, two potential drugs already available in clinical context, could eventually be repositioned towards the treatment of Numb-deficient BCs.