ABSTRACT
The extensive heterogeneity of spontaneously arising human breast cancers has made it difficult to identify specific mechanisms that determine their malignant properties. We now show that invasive tumours developing in immunodeficient mice from freshly isolated normal human mammary cells transduced with a KRASG12D vector show increased expression of the YB-1 RNA-binding protein within two weeks and is sustained in subsequent tumour passages, thus mimicking advanced human breast cancers with KRAS pathway deregulation. YB-1 is also rapidly upregulated in a new de novo model of human ductal carcinoma in situ that we show is obtained from similar xenotransplants of myrAKT1-transduced primary human mammary cells. Knockdown studies demonstrated that YB-1 is essential for both the initial transforming activity of KRASG12D in primary human mammary cells and the metastatic activity of an established human KRASmutant breast cancer cell line. Accompanying molecular and histological analyses indicate YB-1-mediated activation of a HIF1α response.