miR-148b nella progressione del tumore mammario

Breast cancer is often fatal during its metastatic dissemination. To unravel the role of microRNAs (miRs) during malignancy, in Daniela Taverna's lab miR expression has been analyzed in 77 primary breast carcinomas. They identified 16 relapse-associated miRs that correlate with survival and/or distinguish tumor subtypes in different datasets. Among them, miR-148b, downregulated in aggressive breast tumors, was predicted to be a major coordinator of malignancy by bioinformatics tools. In my project, I evaluated how miR-148b was able to coordinate some aspects of tumorigenesis and analyzed miR-148b activity on some of its biological targets. When expression of miR-148b was modulated (up- or down-regulation) in breast cancer cells, in vitro cell growth, adhesion, anoikis, invasion as well as chemotherapy-induced apoptosis were altered. From Daniela Taverna's lab investigations, miR-148b resulted to be able to control malignancy via the coordination of a novel pathway involving over 130 genes (microarray and bioinformatics analyses). We proved that miR-148b is able to target players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, NRAS as well as CSF1, a growth factor for stroma cells, and NRP1, a receptor for VEGF and semaphorin. In parallel, we identified a specific regulatory Feed Forward Loop (FFL) involving ITGA5, miR-148b and the transcription factor C-REL that we are now investigating. Our findings show that miR-148b is able to regulate gene networks that coordinate breast cancer progression and the response to chemotherapy.