Chaperone-mediated autophagy targeting chimeras (CMATAC) for the degradation of ERα in breast cancer

Abstract

Estrogen receptor alpha (ERα/ESR1) is overexpressed in over half of all breast cancers and is considered a valuable therapeutic target in ERα positive breast cancer. Here, we designed a membrane-permeant Chaperonemediated Autophagy Targeting Chimeras (CMATAC) peptide to knockdown endogenous ERα protein through chaperone-mediated autophagy. The peptide contains a cell membrane-penetrating peptide (TAT) that allows the peptide to by-pass the plasma membrane, an αI peptide as a protein-binding peptide (PBD) that binds specifically to ERα, and CMA-targeting peptide (CTM) that targeting chaperone-mediated autophagy. We validated that ERα targeting peptide was able to target and degrade ERα to reduce the viability of ERα positive breast cancer cells. Taken together, our studies provided a new method to reduce the level of intracellular ERα protein via CMATAC, and thus may provide a new strategy for the treatment of ERα positive breast cancer.