A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds Against ERalpha Expressing Breast Cancer Cells

Abstract: 17-estradiol (E2) exerts its physiological effects through the estrogen receptor (i.e.,ER). The E2:ER signaling allows the regulation of cell proliferation. Indeed, E2 sustains theprogression of ER positive (ER+) breast cancers (BCs). The presence of ER at the BC diagnosisdrives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression.Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available.Consequently, the actual challenge is to complement the drugs available to fight ER+ primaryand MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food andDrug Administration (FDA)-approved drugs inhibiting E2:ER signaling to cell proliferation incellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo)and fenticonazole (Fenti) induce ER degradation and prevent ER transcriptional signaling andproliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo andFenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with theCDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “antiestrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents avaluable method to rapidly identify bioactive compounds with anti-estrogenic activity.