Cracking the Vicious Cycle: Targeting Jagged1-Mediated Chemoresistance in Breast Cancer Bone Metastasis

Abstract

In 2016, it is expected that nearly a quarter million new cases of breast cancer will be reported in the United States, and 70 percent of these patients will eventually develop bone metastasis. Jagged1/Notch signaling has previously been shown to promote osteolytic bone metastasis by mediating tumor-stromal interaction. Targeting this pathway can therefore potentially inhibit bone metastatic progression. We thus collaborated with Amgen to generate 15D11, a humanized monoclonal antibody against Jagged1. This study aims to further characterize the role of Jagged1/Notch signaling in breast cancer bone metastasis and evaluate the efficacy of 15D11 in treating breast cancer bone metastasis. Here, we report that 15D11 is e↵ective in targeting Jagged1/Notch signaling in vitro. Moreover, we show that 15D11 sensitizes tumor cells to chemotherapy in vivo and propose a new model for Jagged1/Notch signaling in mediating chemoresistance: chemotherapy induces osteoblast-derived Jagged1, which then engages tumor cells and promotes survival after chemotherapy. This study is the first to establish a critical role for stromal-derived Jagged1 rather than tumor-derived Jagged1 in pro-metastatic signaling in the tumor microenvironment, providing a framework for elucidating additional mechanisms contributing to cancer chemoresistance. Based on our results, we recommend further clinical research to test whether 15D11 improves prognosis by reducing chemoresistance in early stage breast cancer patients.