YB-1 IS REQUIRED FOR THE GENESIS AND METASTATIC CAPACITY OF HUMAN BREAST CANCER

ABSTRACT Breast cancer heterogeneity has made it challenging to elucidate shared mechanisms that underpin properties that are critical to their growth in vivo . Here, we interrogate the role of YB-1 protein in the in vivo tumorigenic activity of de novo well as cell line models of human breast cancer. Short-hairpin RNA-mediated knockdown of YB-1 in MDA-MB-231 cells blocked both their local tumour-forming and lung-colonizing activity in transplanted immunodeficient mice. YB-1 knockdown also revealed its important role at early stages of human mammary cell transformation in the generation of invasive ductal carcinoma and ductal carcinoma in situ produced in mice transplanted with freshly isolated human mammary cells transduced, respectively, with KRAS G12D , or myristoylated-AKT1. Conversely, upregulated expression of YB-1 in the poorly tumorigenic T47D cells enhanced this activity. Mechanistically, reducing YB-1 levels in MDA-MB-231 cells impaired their induction of HIF1α, and G3BP1, known YB-1 translational targets and key elements of a stress-adaptive program.