Breast cancer is a multistep disease controlled by a wide spectrum of genetic and epigenetic changes occurring within a cell as well as environmental influences; and it is the most common malignancy in women worldwide, often fatal because of metastasis dissemination. Aberrant miRNA expression can influence several gene networks and pathways implicated in tumorigenesis and metastasis formation.
To unravel the role of miRNAs during breast cancer progression we investigated miRNA expression in 77 ductal breast carcinoma biopsies and 17 mammoplasties by microarray analysis. Sixteen differentially expressed miRNAs were identified comparing patients with or without disease relapse, within 72 months from surgery. This signature correlates with survival and/or distinguishes tumor subtypes in different datasets.
Among them, miR-148b, down-regulated in aggressive breast tumors, was found to be a major coordinator of malignancy. In fact, it is able to oppose various steps of tumor progression when overexpressed in cell lines by influencing invasion, survival to anoikis, extravasation, lung metastasis formation, and chemotherapy response. miR-148b controls malignancy by coordinating a novel pathway involving over 130 genes and, in particular, it directly targets players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, and NRAS, as well as CSF1, a growth factor for stroma cells.
Our findings reveal the importance of the identified 16 miRNAs for disease outcome predictions and suggest a critical role for miR-148b in the control of breast cancer progressio
