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

17 beta-estradiol (E2) exerts its physiological effects through the estrogen receptor alpha (i.e., ER alpha). The E2:ER alpha signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ER alpha positive (ER alpha+) breast cancers (BCs). The presence of ER alpha at the BC diagnosis drives 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 alpha+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ER alpha signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ER alpha degradation and prevent ER alpha transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as anti-estrogens-like drugs. Remarkably, the present anti-estrogen discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

Automated summary

17 beta-estradiol acts through estrogen receptor alpha to regulate cell proliferation and sustain the progression of ER alpha positive breast cancers. Using an anti-estrogen discovery platform, new FDA-approved drugs like clotrimazole and fenticonazole have been identified to inhibit E2:ER alpha signaling, preventing ER alpha transcriptional signaling and proliferation in primary and metastatic BC cells. These drugs also show anti-proliferative effects in 3D cancer models and synergize with CDK4/CDK6 inhibitors.