Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer

Abstract

In estrogen receptor positive (ER+) breast cancer therapy, estrogen receptors (ERs) are the major targeting molecules. ER-targeted therapy has provided clinical benefits for approximately 70% of all breast cancer patients through targeting the ERα subtype. In recent years, mechanisms underlying breast cancer occurrence and progression have been extensively studied and largely clarified. The PI3K/AKT/mTOR pathway, microRNA regulation, and other ER downstream signaling pathways are found to be the effective therapeutic targets in ER+ BC therapy. A number of the ER+ (ER+) breast cancer biomarkers have been established for diagnosis and prognosis. The ESR1 gene mutations that lead to endocrine therapy resistance in ER+ breast cancer had been identified. Mutations in the ligand-binding domain of ERα which encoded by ESR1 gene occur in most cases. The targeted drugs combined with endocrine therapy have been developed to improve the therapeutic efficacy of ER+ breast cancer, particularly the endocrine therapy resistance ER+ breast cancer. The combination therapy has been demonstrated to be superior to monotherapy in overall clinical evaluation. In this review, we focus on recent progress in studies on ERs and related clinical applications for targeted therapy and provide a perspective view for therapy of ER+ breast cancer.

Keywords: biomarkers; clinical trials; combination therapy; endocrine therapy; estrogen receptor; estrogen receptor-positive breast cancer; mutation; resistance mechanisms; targeted therapy.

Figure 1.

Domain structure of ERα and ERβ. Basic modular domain structure and functions of ERα and ERβ is very similar. The domain similarity of the 2 receptors is: the N-terminal domain (NTD; A-/B-domain) 17%; the DBD (C-domain) 97%; the hinge region (D-domain) 36%; the LBD (E-domain) 56%; and the CTD (F-domain) 18%, respectively. All the domains of the 2 receptors undergo PTMs. Some of domains are involved in PPIs, such as interaction with coregulator proteins. Both ERα and ERβ contain a NLS in the hinge domain. In addition, the NTD of ERβ has no AF1 activity, suggesting that ERβ may not have the ligand-independent transcriptional activity. Abbreviations: DBD, DNA-binding domain; LBD, ligand-binding domain; CTD, C-terminal domain; PTM, posttranslational modification; PPI, protein–protein interaction; NLS, nuclear localization signal; NTD, N-terminal domain; ER, estrogen receptor.

Figure 2.

The most common mutations occur in the LBD of ERα. Approximately 80% of mutations are D538G, Y537S, Y537N, Y537C, or E380Q, located in the LBD of ERα. Abbreviations: LBD, ligand-binding domain; ER, estrogen receptor.