Breast cancer is the most common cancer and the most frequent cause of cancer related mortality among women worldwide. In recent years, major strides in breast cancer research have propelled advances in diagnostic and therapeutic tools that, in turn, have led to improvements in breast cancer survival rates. However, several critical stages of breast cancer remain poorly understood, including ductal carcinoma in situ (DCIS) as well as cancer recurrence after therapy. Here, using genetically engineered mouse models that faithfully recapitulate these processes as they occur in women, we demonstrate that Notch signaling plays a role in both the formation of DCIS and in the recurrence of invasive breast cancers following HER2/neu targeted therapy. First to investigate the role of Notch signaling in early stages of breast cancer progression as well as mammary epithelial cell fate determination, we generated transgenic mice in which Notch signaling is activated in the mammary epithelium upon doxycycline administration. We found that Notch signaling promotes the expansion of mature luminal epithelial cells resulting in ductal lesions that closely resemble micropapillary DCIS in humans. Next, using this model to generate an expression signature that classifies human breast cancers according to their predicted levels of Notch activity, we demonstrated that Notch signaling is associated with an elevated risk of recurrence in women with breast cancer. To determine whether Notch signaling plays a functional role in breast cancer recurrence, we used genetic and pharmacological approaches to activate or inhibit Notch signaling in a mouse model of HER2/neu targeted therapy. These experiments revealed that upregulation of endogenous Notch signaling following HER2/neu inhibition promotes the survival and recurrence of dormant residual tumor cells. Together, our results identify new roles for Notch signaling in regulating distinct stages of breast cancer progression and suggest that inhibition of Notch signaling may be effective in treating DCIS and limiting breast cancer recurrence
