Novel Breast Cancer Treatment by Targeting Estrogen Receptor-Alpha Stability Using Proteolysis-Targeting Chimeras (PROTACs) Technology

Abstract

Approximately 70% of breast cancer cases are estrogen receptor-alphapositive (ERα+). The binding of estradiol to the ligand-binding domain activates ERα. ERα can also be activated via the phosphorylation induced by growth factors. Activated ERα functions as a transcriptional regulator with a pro-tumor activity in breast cancer cells. In recent years, it has been discovered that some proteins can stabilize ERα by inhibiting its degradation via the ubiquitin-proteasome system through several mechanisms, including ERα monoubiquitination, deubiquitination, or phosphorylation, among others. Herein, we review the proteins associated with the inhibition of ERα degradation and discuss the role of proteolysis-targeting chimeras (PROTACs) as promising therapeutic strategies for breast cancer by inducing ERα degradation. The knowledge of the multiple mechanisms that stabilize ERα protein may be central for the development of new PROTACs for novel breast cancer treatments.