This study reveals a coordinative transcriptional regulation of CD47 and HER2 in radioresistant BC cells. Expression of both CD47 and HER2 is enhanced in irradiated BC cells, in RT-treated mouse syngeneic breast tumors, and in BC patients with recurrent diseases associated with a poor prognosis. Blocking CD47 not only enhances macrophages-mediated phagocytosis but also suppresses HER2-associated aggressiveness in the radioresistant BC cells, which is recapitulated using mouse syngeneic BC that can be synergistically suppressed by RT with inhibition of both receptors. These results demonstrate a latent pro-tumor growth mechanism due to the cross-talking of CD47-enhanced immune-avoidance with HER2-promoted intrinsic cell proliferation, causing the aggressive behavior of resistant BC cells. Dual blocking CD47 and HER2 may effectively abolish resistant cancer cells in BC radiotherapy.

Demet Candas-Green, Bowen Xie, Jie Huang, Ming Fan, Aijun Wang, Cheikh Menaa, Yanhong Zhang, Lu Zhang, Di Jing, Soheila Azghadi, Weibing Zhou, Lin Liu, Nian Jiang, Tao Li, Tianyi Gao, Colleen Sweeney, Rulong Shen, Tzu-yin Lin, Chong-xian Pan, Omer M. Ozpiskin, Gayle Woloschak, David J. Grdina, Andrew T. Vaughan, Ji Ming Wang, Shuli Xia, Arta M. Monjazeb, William J. Murphy, Lun-Quan Sun, Hong-Wu Chen, Kit S. Lam, Ralph R. Weichselbaum, Jian Jian Li