Targeting estrogen receptor alpha in breast cancer for novel therapies resistance mechanisms and future directions

Estrogen receptor α (ERα) is a key therapeutic target in ER-positive breast cancer. Structurally, ERα contains activation function (AF) domains that drives breast cancer proliferation, metastasis, and drug resistance through classical genomic, non-genomic, and ligand-independent signaling pathways. Clinically approved and investigational drugs targeting Erα include selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators/degraders (SERDs), and novel strategies such as proteolysis-targeting chimeras (PROTACs). Current research focuses on overcoming endocrine resistance via combination therapies targeting mutations in ESR1, the gene encoding ERα, non-genomic signaling pathways, and the tumor microenvironment, which may advance precision medicine in breast cancer. This article summarizes recent advances in ERα-targeting inhibitors and their therapeutic implications, to provide potential precision therapeutic strategies for breast cancer patients with ER positive.