Unexpected Impact of a Hepatitis C Virus Inhibitor on 17beta-Estradiol Signaling in Breast Cancer

17-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor (ER). E2:ER signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ER abundance. Indeed, the control of ER levels is necessary for the eects of E2, and E2 itself induces ER degradation and cell proliferation in parallel. Thus, the modulation of intracellular ER levels is a critical parameter for E2-induced cell proliferation. Therefore, we used this parameter as a bait to identify compounds that influence ER levels and E2-dependent proliferation in breast cancer (BC) cells from a library of Food and Drug Administration (FDA)-approved drugs. We found that telaprevir (Tel) reduces ER levels and inhibits BC cell proliferation. Tel is an inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease, but its eect on E2:ER signaling has not been investigated. Here, for the first time, we analyzed the eects of Tel on intracellular ER levels and E2:ER signaling to cell proliferation in dierent ER-expressing BC cell lines. Overall, our findings demonstrate that Tel reduces intracellular ER levels, deregulates E2:ER signaling and inhibits E2-induced proliferation in BC cells and suggest the potential drug repurposing of Tel for the treatment of BC.