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.
Highlights
The estrogen receptor (ER) is the main downstream effector of its ligand estrogen and has functions connected to the menstrual cycle, pregnancy, and lactation in females and in maintaining cardiovascular, nervous, musculoskeletal, and immune system functioning [1]
ER mutants enhances interaction with insulin-like growth factor 1 (IGF-1) and is associated with constitutive phosphorylation of IGF-1 and insulin receptor substrate (IRS); promoting cell growth [33]. This cell growth is reduced by inhibiting IGF-1 receptor (IGF-1R) with the tyrosine kinase inhibitor, Tyrphostin AGTreatment with both the aromatase inhibitors (AIs) substrate androstenedione and IGF-1 resulted in greater growth of K303R mutant cells, than with either of these ligands independently [33]
ER signaling remains central to the treatment of ER positive breast cancer (BCa), and posttranslational modifications (PTMs) play a significant role in determining responses to endocrine therapies (ETs), alongside ESR1/ER mutations
Summary
The estrogen receptor (ER) is the main downstream effector of its ligand estrogen and has functions connected to the menstrual cycle, pregnancy, and lactation in females and in maintaining cardiovascular, nervous, musculoskeletal, and immune system functioning [1]. Inhibitors (AIs)of localisation, Coactivator binding Degradation and target gene Coactivator binding and target gene (PGR, c-Myc, GREB1) transcription, Addition of Receptor Modifiers. For BCa treatment using endocrine therapies (ETs) including tamoxifen, fulvestrant, and aromatase inhibitors [11] (see below), in both scenarios promoting cell proliferation and suppressing common target for BCa treatment using endocrine therapies (ETs) including tamoxifen, fulvestrant, inactive complex, by preventing coactivator interactions [12,13,14,15]. Whilst these are initially for have manybeen functionally characterised and remains confer akey attributes associated with ET resistance, indicating positive. ET(Figure resistance, Since a major control of activity is through regulation of its half-life, changes mechanistic roles in resistance such as estrogen independence, increased transcriptiontoofER. Posttranslational modifications (PTMs) and ESR1 mutations causing amino acid substitutions at PTM sites may influence ER stability, and activity
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