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Review
. 2015 Oct;12(10):573-83.
doi: 10.1038/nrclinonc.2015.117. Epub 2015 Jun 30.

ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer

Affiliations
Review

ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer

Rinath Jeselsohn et al. Nat Rev Clin Oncol. 2015 Oct.

Abstract

Approximately 70% of breast cancers are oestrogen receptor α (ER) positive, and are, therefore, treated with endocrine therapies. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. Despite the magnitude of this clinical challenge, the mechanisms underlying the development of resistance remain largely unknown. In the past 2 years, several studies unveiled gain-of-function mutations in ESR1, the gene encoding the ER, in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies, such as tamoxifen and aromatase inhibitors. These mutations are clustered in a 'hotspot' within the ligand-binding domain (LBD) of the ER and lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity; thus, ER LBD mutations might account for a mechanism of acquired endocrine resistance in a substantial fraction of patients with metastatic disease. In general, the absence of detectable ESR1 mutations in patients with treatment-naive disease, and the correlation between the frequency of patients with tumours harbouring these mutations and the number of endocrine treatments received suggest that, under selective treatment pressure, clonal expansion of rare mutant clones occurs, leading to resistance. Preclinical and clinical development of rationale-based novel therapeutic strategies that inhibit these ER mutants has the potential to substantially improve treatment outcomes. We discuss the contribution of ESR1 mutations to the development of acquired resistance to endocrine therapy, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes.

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Conflict of interest statement

Competing Interests

RS has received research funding from AstraZenca and GlaxoSmithKline. MB has received a commercial research grant and is a consultant/advisory board member for Novartis Pharmaceuticals.

Figures

Figure 1
Figure 1. Schematic representation of the recently published sequencing studies of ER+ metastatic breast cancer and related primary tumors
Numbers of sequenced metastatic and primary breast cancer samples and reported ESR1 LBD point mutations (*) are indicated. The dashed lines indicate primary tumors that were sequenced subsequently to the detection of the ESR1 LBD mutation in their matched metastatic specimens. The ER+ BC cohort from Jeselsohn’s study included upfront 37 matched ER+ metastatic and primary sample pairs, of which in 2 of these pairs (#) ESR1 LBD mutations were detected in the metastatic but not in the primary tumors. Abbreviations: BC, breast cancer; BOLERO-2, Breast cancer trials of OraL EveROlimus-2; Met, metastatic samples; MI-ONCOSEQ, the MIchigan ONCOlogy SEQuencing program; MSKCC, Memorial Sloan Kettering Cancer Center; PDXs, Patient-derived xenografts.
Figure 2
Figure 2. Structural/functional diagram of the ESR1 ERα protein product with the position and number of cases of the ESR1 ligand-binding domain (LBD) point mutations reported in metastatic ER+ breast cancers
Black circles indicate each mutation at the specific protein position; numbers in parentheses indicate the total number of samples reported to harbor the specific indicated mutations. Abbreviations: AF-1, activation function-1; DBD, DNA-binding domain; AF-2, activation function-2.
Figure 3
Figure 3. Genomic classical and non-classical transciptional activities of E2-stimultated wild-type ER and ligand-independent mutant ER and potential novel therapeutics
Classical ER transcription activity is mediated by ER binding to DNA at the consensus ERE sites, while in the non-classical ER activity mode, the receptor is tethered to other transcriptional factors such as AP-1 or NFkB and regulates gene expression from their sites. The transcriptional activity of ER and other TFs is further modulated by RTKs and other signaling pathway-induced kinases (e.g., MAPK and AKT) that phosphorylate ER, its coregulatory proteins (e.g., CoA), and other components of the transcriptional machinery to control the overall transcriptional program needed for tumor development and progression. Differential expression profiles between wild-type and mutant ERs suggest an augmented non-classical genomic activity of ER mutants, which may enhance RTK signaling and the metastatic capacity of the tumor cells. Breast cancer cells with wild-type ER (A) are largely sensitive to standard endocrine therapies (aromatase inhibitors, tamoxifen, fulvestrant). In contrast, ESR1 LBD mutant cells (B) display an endocrine resistant phenotype and current findings suggest the need of alternative therapeutic strategies such as higher doses of fulvestrant or tamoxifen, more potent or mutant specific SERMS or SERDs (bazedoxifene and ARN-810, respectively), agents targeting ER co-activators and ER gene products such as, cyclinD1 blockade by CDK4/6 inhibitors, or other signaling pathways and kinase inhibitors (e.g., mTOR, PI3Kinase, and HSP90 inhibitors) alone or in combination with ER inhibitors. Abbreviation: AIs, aromatase inhibitors; BZD, bazedoxifen; CoA, co-activator; ER, estrogen receptor; ERE, estrogen responsive element; Ful, fulvestrant; i, inhibitor; LBD, ligand-binding domain; RTKs, tyrosine kinase receptors; Tam, tamoxifen; TFs, transcription factors.
Figure 3
Figure 3. Genomic classical and non-classical transciptional activities of E2-stimultated wild-type ER and ligand-independent mutant ER and potential novel therapeutics
Classical ER transcription activity is mediated by ER binding to DNA at the consensus ERE sites, while in the non-classical ER activity mode, the receptor is tethered to other transcriptional factors such as AP-1 or NFkB and regulates gene expression from their sites. The transcriptional activity of ER and other TFs is further modulated by RTKs and other signaling pathway-induced kinases (e.g., MAPK and AKT) that phosphorylate ER, its coregulatory proteins (e.g., CoA), and other components of the transcriptional machinery to control the overall transcriptional program needed for tumor development and progression. Differential expression profiles between wild-type and mutant ERs suggest an augmented non-classical genomic activity of ER mutants, which may enhance RTK signaling and the metastatic capacity of the tumor cells. Breast cancer cells with wild-type ER (A) are largely sensitive to standard endocrine therapies (aromatase inhibitors, tamoxifen, fulvestrant). In contrast, ESR1 LBD mutant cells (B) display an endocrine resistant phenotype and current findings suggest the need of alternative therapeutic strategies such as higher doses of fulvestrant or tamoxifen, more potent or mutant specific SERMS or SERDs (bazedoxifene and ARN-810, respectively), agents targeting ER co-activators and ER gene products such as, cyclinD1 blockade by CDK4/6 inhibitors, or other signaling pathways and kinase inhibitors (e.g., mTOR, PI3Kinase, and HSP90 inhibitors) alone or in combination with ER inhibitors. Abbreviation: AIs, aromatase inhibitors; BZD, bazedoxifen; CoA, co-activator; ER, estrogen receptor; ERE, estrogen responsive element; Ful, fulvestrant; i, inhibitor; LBD, ligand-binding domain; RTKs, tyrosine kinase receptors; Tam, tamoxifen; TFs, transcription factors.
Figure 4
Figure 4. Clonal selection of rare ESR1 mutations in acquired endocrine-resistant ER+ breast cancer
Two possible scenarios for the origin of the ESR1 LBD mutations detected endocrine resistant metastatic breast cancer are proposed: Pre-existing rare ESR1 LBD mutant subclones (red x) in treatment-naïve primary tumors (A) or acquired de novo ESR1 mutations during therapy (B). In both cases, a selection and an expansion of the ESR1 mutant clones occurs over multiple lines of endocrine therapy (violet triangle) leading to an acquired endocrine-resistant phenotype.
Figure 5
Figure 5
Future clinical directions in understanding the clinical significance of the ESR1 LBD mutations and novel therapeutics.

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