Simple SummaryER+ breast cancer is the most diagnosed subtype and patient prognosis has improved in recent years thanks largely to the development of endocrine-targeting therapies including tamoxifen. Unfortunately, many tumors will recur as endocrine-therapy-resistant metastases. Therefore, in order to prolong resistance-free survival, combination therapies that mitigate resistance mechanisms should be pursued. In this study, we tested 516 drug combinations with tamoxifen and identified two that were synergistic. These combinations inhibited breast cancer patient-derived xenograft (PDX) growth in animal models better than either drug or tamoxifen alone.AbstractBreast cancer alone accounts for the majority of cancer deaths among women, with the most commonly diagnosed subtype being estrogen receptor positive (ER+). Survival has greatly improved for patients with ER+ breast cancer, due in part to the development of antiestrogen compounds, such as tamoxifen. While treatment of the primary disease is often successful, as many as 30% of patients will experience recurrence and metastasis, mainly due to developed endocrine therapy resistance. In this study, we discovered two tamoxifen combination therapies, with simeprevir and VX-680, that reduce the tumor burden in animal models of ER+ breast cancer more than either compound or tamoxifen alone. Additionally, these tamoxifen combinations reduced the expression of HER2, a hallmark of tamoxifen treatment, which can facilitate acquisition of a treatment-resistant phenotype. These combinations could provide clinical benefit by potentiating tamoxifen treatment in ER+ breast cancer.