Ricerc@Sapienza

Solid tumors often survive in hypoxic microenvironment, a stress condition which affects the functionality of the endoplasmic reticulum (ER), determining the "ER stress" condition. Unfolded protein response (UPR) is the adaptive response which restores protein homeostasis after ER stress, contributing to tumor survival. Recent studies highlighted the role of UPR in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype, where UPR targeting, through IRE1alpha-XBP1 pathway inhibition, has been suggested as a promising therapeutic approach. XBP1 has a pivotal role in progression and invasiveness of TNBC representing a specific prognostic value for TNBC patients. For this reason, XBP1 downregulation increases the sensitivity of transformed cells to be killed by hypoxia. Aberrant Notch signaling is a common feature of pathogenesis and progression of TNBCs, leading to the employment of Notch inhibitors in TNBC therapy. Recently, in T-cell acute lymphoblastic leukemia context, we demonstrated that Notch3 sustains UPR pathway through a positive regulation of IRE1alpha-XBP1 axis. Our proposal is to demonstrate an involvement of Notch3 signaling in the regulation of the IRE1alpha-XBP1-mediated UPR in response to hypoxia in TNBCs, thus providing a rationale for using Notch3 inhibition as a therapeutic strategy to affect UPR, finally inducing TNBC cell death.