Significance Tumors are composed of both cancer stem-like cells (CSCs) and differentiated cancer cells. Each CSC can undergo either a symmetric cell division to produce two CSCs or an asymmetric cell division to produce one CSC and one differentiated cancer cell. It is believed that the rate of symmetric division increases as more CSCs become malignant; however, underlying molecular mechanisms remain elusive. Here we show that stimulation with a cytokine, semaphorin (Sema), activates monooxygenase of MICAL3, a cytoplasmic signal transducer, through the neuropilin (NP) receptor that is specifically expressed on the breast CSC plasma membrane. The activation of MICAL3 induces symmetric division of CSCs. Each molecule in this signaling pathway represents a promising therapeutic target for eliminating CSCs.