While previous studies have reported the role of ER, and ERBB pathways in endocrine resistance, our study clarifies the role of SMAD4 in orchestrating ER, and ERBB signaling pathways, which provides a novel perspective on the development of acquired endocrine resistance and suggests that combined inhibition of ER activity, ERBB signaling, and autophagic process may be a rational therapeutic strategy for patients with acquired endocrine-resistant breast cancer. Here, ESR1 is linked to breast cancer.