Strategies to degrade estrogen receptor α in primary and ESR1 mutant-expressing metastatic breast cancer

Abstract With the advent of omic technologies, our understanding of the molecular mechanisms underlying estrogen receptor α (ERα)-expressing breast cancer (BC) progression has grown exponentially. Nevertheless, the most widely used therapy for inhibiting this disease is endocrine therapy (ET) ( i.e., aromatase inhibitors, tamoxifen - Tam, faslodex/fulvestrant - FUL). However, in a considerable number of cases, prolonged patient treatment with ET generates the development of resistant tumor cells and, consequently, tumor relapse, which manifests as metastatic disease that is extremely difficult to manage, especially because such metastatic BCs (MBCs) often express ERα mutations ( e.g., Y537S, D538G) that confer pronounced growth advantages to tumor cells. Interestingly, ET continues to be the therapy of choice for this neoplasia, which underscores the need to identify novel drugs that could work in primary and MBCs. In this study, we review the approaches that have been undertaken to discover these new anti-ERα compounds, especially considering those focused on evaluating ERα degradation. A literature analysis demonstrated that current strategies for discovering new anti-BC drugs are focusing on the identification either of novel ERα inhibitors, of compounds that inhibit ERα-related pathways or of drugs that influence ERα-unrelated cellular pathways. Several lines of evidence suggest that all of these molecules alter the ERα content and block the proliferation of both primary and MBCs. In turn, we propose to rationalize all these discoveries into the definition of e.m.eral.d.s ( i.e., s e lective m odulators of ERα l evels and d egradation) as a novel supercategory of anti-ERα drugs that function both as modulators of ERα levels and inhibitors of BC cell proliferation.