Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability

Abstract

Therapy of hormone receptor positive breast cancer (BCa) generally targets estrogen receptor (ER) function and signaling by reducing estrogen production or by blocking its interaction with the ER. Despite good long-term responses, resistance to treatment remains a significant issue, with approximately 40% of BCa patients developing resistance to ET. Mutations in the gene encoding ERα, ESR1, have been identified in BCa patients and are implicated as drivers of resistance and disease recurrence. Understanding the molecular consequences of these mutations on ER protein levels and its activity, which is tightly regulated, is vital. ER activity is in part controlled via its short protein half-life and therefore changes to its stability, either through mutations or alterations in pathways involved in protein stability, may play a role in therapy resistance. Understanding these connections and how ESR1 alterations could affect protein stability may identify novel biomarkers of resistance. This review explores the current reported data regarding posttranslational modifications (PTMs) of the ER and the potential impact of known resistance associated ESR1 mutations on ER regulation by affecting these PTMs in the context of ET resistance.

Keywords: ESR1; breast cancer; endocrine therapy; posttranslational modifications; proteasome.

Figure 1

ERα functional domains. The ERα functional domains include; Activation Function 1 (AF-1) (purple), DNA Binding Domain (DBD) (blue), hinge (pink), Ligand Binding Domain (LBD) and AF-2 (plum).

Figure 2

Estrogen Receptor Signalling and ER Targeting Treatment. Aromatase converts androgens to estrogens, Estrogen receptor binds estrogen, Dimerisation, Post translational modification, Nuclear localisation, Coactivator binding and target gene (PGR, c-Myc, GREB1) transcription, Addition of ubiquitin by E1, E2 & E3 ligases, Degradation by the 26S proteasome. Aromatase Inhibitors (AIs) inhibit the enzyme aromatase, Selective Estrogen Receptor Degraders (SERDs) and Selective Estrogen Receptor Modifiers (SERMs) prevent estrogen binding.

Figure 3

Post translational modifications of ERα. The ERα functional domains include: Activation Function 1 (AF-1) (purple), DNA Binding Domain (DBD) (blue), hinge (pink), Ligand Binding Domain (LBD) and AF-2 (plum). At the top of the schematic are known sites PTMs of ERα; phosphorylation (P, dark blue), SUMOylation (S, orange), methylation (M, light blue), acetylation (A, red), ubiquitylation (U, yellow), pamiltoylation (Pa, green) and gycosylation (G, purple). At the bottom are PTM sites affected by ESR1 mutations.