In this report, we uncovered a ligand–receptor pair of hRNase 1–EphA4 critical for breast cancer initiation, namely that hRNase 1 acts as a natively secretory ligand of EphA4 to stimulate EphA4 signaling in an autocrine/paracrine manner, leading to upregulation of stem-like cell properties in breast cancer. Here, EPHA4 is linked to breast cancer.