This study provides new molecular and functional evidence supporting the role of ESR1-CCDC170 in reducing endocrine responsiveness in breast cancer cells in vitro and in vivo and revealed a novel action mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC complex and activates their downstream signaling to endow cancer cell survival under endocrine therapy. The gene discussed is ERBB2; the disease is breast cancer.