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.

Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy

“…12 It is now clear that mechanisms of resistance include aberrations in the expression of ER leading to the up-regulation of its downstream pathways. 26 Mutation in the ESR1 gene coding for ER occurred in 20%-40% of metastatic breast cancers treated by ET. 12 An interruption of this treatment could allow the loss of the mutation or delay its appearance and subsequent resistance.…”

Prognostic and Predictive Value of CCND1/Cyclin D1 Amplification in Breast Cancer With a Focus on Postmenopausal Patients: A Systematic Review and Meta-Analysis

“…The Cyclin D1-CDK4 or 6 complex phosphorylates the Rb, leading to disassociation of Rb from E2F1, thus activating G 1 /S phase gene transcription and cell cycle progression (5) (Figure 1). Growth factor signalling pathways, PI3K-AKT-mTOR and MAPK, are linked with both cyclin D1 and Estrogen Receptor (ER) activity (6,7). There is interplay between the ER, CCND1 gene and cyclin D1 protein whereby the ER promotes transcription of the CCND1 gene, and the cyclin D1 protein interacts with the ER to promote ER mediated transcription (8)(9)(10).…”

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

“…This review will discuss specifically the mechanism controlling ERα expression levels in normal and breast cancer cells. Other mechanisms of resistance to hormonal therapies, which include activation of other proliferative pathways and modulation of ERα or coregulator activity via genetic or epigenetic alterations, have been reviewed elsewhere (e.g., [ 7 , 9 , 10 , 11 ]).…”

“…Both receptors are nevertheless activated by circulating estrogens, which trigger conformational changes in the ligand binding domain inducing receptor binding to DNA and recruitment of a variety of transcriptional coactivators or co-repressors [ 12 , 15 , 34 , 35 , 36 , 37 , 38 ]. The two receptors diverge more in other domains ( Figure 1 a), and as a result differ in their functional properties [ 39 ] and in their regulation by post-translational modifications (please refer to Phosphosite.org for a summary of ERα/β post-translational modifications and to [ 11 , 40 , 41 ] for reviews). Modifications can affect diverse ER functional properties, including subcellular localization, DNA binding, interaction with other transcriptional regulators or chromatin components, and protein stability.…”