Our findings demonstrate that ESR1 mutations provide an important, albeit not the only driver of acquired endocrine resistance, concordant with the clinical observation that ~20% of metastatic tumors harbor mutant ESR1. Using resistance models featuring ESR1 mutations and those that do not involve ESR1 mutations should prove to be valuable in aiding patient management, and for assessing new treatment approaches for endocrine-resistant BC. Here, ESR1 is linked to breast cancer.