Loss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promoting uncontrolled proliferation. The role polarity proteins play during tumorigenesis in mammals is poorly understood. We demonstrate that knockdown of Scribble in mammary epithelia disrupts cell polarity, blocks three-dimensional morphogenesis, inhibits apoptosis and induces dysplasia in vivo that progress to tumors after long latency. Knockdown of Scribble also cooperates with oncogenes such as Myc to transform epithelial cells in 3D acini and induce tumors in vivo by blocking activation of an apoptosis pathway. Like knockdown, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation. Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated and mislocalized Scribble suggesting a selection-pressure for Scribble inactivation. Thus, we demonstrate that Scribble is a novel regulator of breast cancer and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death.