Abstract

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα 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 ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα 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 ERα degradation and prevent ERα 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.

Highlights

  • The sex hormone 17β-estradiol (E2) exerts pleiotropic physiological effects through its binding to the estrogen receptor α (i.e., ERα), which is a ligand-activated transcription factor

  • According to the characterized by different molecular alterations, approximately 75% of breast cancers (BCs) are E2-dependNational Cancer Institute (NIH), in 2020 BC has represented 15.3% of all new cancer cases ent tumors characterized by high expression of the ERα

  • E2:ERα signaling to cell proliferation endocrine therapy (ET) represents a validated pharmacological strategy disease characterized by different molecular alterations, approximately 75% of BC are E2for the management of early and advanced ERα+ BC

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Summary

Introduction

The sex hormone 17β-estradiol (E2) exerts pleiotropic physiological effects through its binding to the estrogen receptor α (i.e., ERα), which is a ligand-activated transcription factor. The binding of E2 to the receptor activates gene transcription. The E2-dependent association of the ERα to millions of regulatory sites on chromatin (i.e., promoters containing or not containing the estrogen-responsive-element (ERE) sequence) exerts direct control on gene expression, which is further modulated by the ability of the ERα to be recruited in different chromatin multi-protein complexes. These receptor interactors are specific transcriptional co-regulators, which contribute to the modulation of E2-induced gene transcription [1].

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