Abstract A32: Notch signaling regulates recurrence in a model of HER2 targeted therapy

Abstract

Abstract Breast cancer is the leading cause of cancer-related deaths among women worldwide. While mortality rates have improved over the past thirty years, physicians still lack effective tools for the prevention or treatment of breast cancer recurrence. An essential first step in designing such therapies will be to elucidate the pathways that contribute to therapeutic resistance, dormancy, and recurrence. Our laboratory has developed a series of mouse models that permit the conditional activation of oncogenes in the mammary glands of mice and can be used to recapitulate key features of breast cancer progression including dormancy and recurrence after targeted therapy. In the MMTV-rtTA;TetO-neu (MTB/TAN) model, treatment with doxycycline (dox) permits mammary specific activation of HER2/neu and drives primary tumor formation. Upon removal of dox and resultant down-regulation of HER2/neu, primary tumors regress as a consequence of oncogene addiction. However, a small population of tumor cells persists in a histologically identifiable residual lesion. After a period of cellular dormancy, residual tumor cells reenter the cell cycle in a stochastic manner and give rise to recurrent tumors, independent of HER2/neu signaling. Recent evidence suggests that Notch signaling may play a role in breast cancer recurrence. For example, elevated Notch signaling in ductal carcinoma in situ lesions has been found to be associated with early recurrence after surgery. To build on these data, we analyzed microarray datasets from breast cancer patients and found that NOTCH1 expression levels are correlated with recurrence risk, suggesting that this pathway may play a role in human disease. Furthermore, in our mouse model system, we have found that Notch signaling is activated following HER2/neu downregulation. To assess the functional significance of this phenomenon, we performed in vitro clonogenic assays and in vivo recurrence assays. Activation of Notch signaling accelerated colony formation and recurrence, whereas Notch repression inhibited colony formation and recurrence. These data suggest that Notch signaling is both necessary and sufficient to promote recurrence following HER2/neu downregulation. Taken together, our data support a model in which the Notch signaling pathway provides a mechanism by which HER2/neu driven tumors can escape therapy and cause recurrent disease. As gamma secretase inhibitors are currently in late-stage clinical trials for the treatment of breast cancer, work to determine whether Notch signaling contributes to the survival and recurrence of breast cancer cells could have a significant clinical impact. The observation that Notch signaling is required for recurrence would raise the possibility that these drugs could be used to target residual tumor cells and prevent breast cancer recurrence.