Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance

Martin, Lesley-Ann; Ribas, Ricardo; Simigdala, Nikiana; Schuster, Eugene; Pancholi, Sunil; Tenev, Tencho; Gellert, Pascal; Buluwela, Laki; Harrod, Alison; Thornhill, Allan; Nikitorowicz-Buniak, Joanna; Bhamra, Amandeep; Turgeon, Marc-Olivier; Poulogiannis, George; Gao, Qiong; Martins, Vera; Hills, Margaret; García-Murillas, Isaac; Fribbens, Charlotte; Patani, Neill; Li, Zheqi; Sikora, Matthew J.; Turner, Nicholas C.; Zwart, Wilbert; Oesterreich, Steffi; Carroll, Jason S.; Ali, Simak; Dowsett, Mitch

doi:10.1038/s41467-017-01864-y

Cited by 123 publications

(134 citation statements)

References 45 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…[20][21][22] Using in vitro-derived ESR1 mutant cell line models generated using CRISPR/Cas9 technology, or through natural selection of cells in hormone-deprived conditions, Martin et al 23 showed that there was a high overlap between ER chromatin binding sites of estrogen-stimulated WT receptor and hormone-deprived mutant receptors. [20][21][22] Using in vitro-derived ESR1 mutant cell line models generated using CRISPR/Cas9 technology, or through natural selection of cells in hormone-deprived conditions, Martin et al 23 showed that there was a high overlap between ER chromatin binding sites of estrogen-stimulated WT receptor and hormone-deprived mutant receptors.…”

Section: Biology Of Esr1 Mutations In Preclinical Studiesmentioning

confidence: 99%

“…For instance, Martin et al 23 were the first to model in vitro the natural acquisition of ESR1 mutations in ER-positive breast cancer cells. For instance, Martin et al 23 were the first to model in vitro the natural acquisition of ESR1 mutations in ER-positive breast cancer cells.…”

Section: Biology Of Esr1 Mutations In Preclinical Studiesmentioning

confidence: 99%

“…20,25 These mutations are rare or are not present in primary tumors. 20,23 10,26 Gu et al 25 were the first to report that the Y537S ESR1 mutation drives spontaneous ligand-independent distant metastasis in vivo using CRISPR-Cas9 engineered ESR1 mutant xenograft models.…”

Section: Implications Of Esr1 Mutations In Metastasis and Tumor Progrmentioning

confidence: 99%

“…The transcriptomes of WT and mutant ERs have been described by several groups, showing there are shared, classical ER signaling signatures, as well as mutant-specific transcriptional regulation. [20][21][22] Using in vitro-derived ESR1 mutant cell line models generated using CRISPR/Cas9 technology, or through natural selection of cells in hormone-deprived conditions, Martin et al 23 showed that there was a high overlap between ER chromatin binding sites of estrogen-stimulated WT receptor and hormone-deprived mutant receptors. They further showed that estrogen treatment of both the WT and Y537S models exhibited a 74% concordance in ER binding sites.…”

Section: Introductionmentioning

confidence: 99%

“…Other studies have extended clinical findings of acquired ESR1 mutations in hormone-deprived MBC patients by confirming these observations in 2-dimensional culture systems. For instance, Martin et al 23 were the first to model in vitro the natural acquisition of ESR1 mutations in ER-positive breast cancer cells. Culturing breast cancer cells with WT ESR1 for the long term in hormone-depleted media resulted in gradual acquisition of the Y537C mutation in MCF-7 cells and the Y537S mutation in SUM44 cells.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

ESR1 mutations in breast cancer

Dustin

Fuqua

2019

Cancer

194

131

View full text Add to dashboard Cite

The acquisition of ligand-independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)-positive breast cancer is a common mechanism of hormonal therapy resistance. Preclinical and clinical studies have demonstrated that ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis. Several groups have used sensitive detection methods using patient liquid biopsies to track ESR1 or truncal somatic mutations to predict treatment outcome and tumor progression, and some of these techniques may eventually be used to guide sequential treatment options in patients. Further development and standardization of mutation tracking in circulating tumor DNA is ongoing. Clinically, patients with ESR1 mutations derive clinical benefit when treated with fulvestrant and CDK4/6-targeted therapies, but the development of more potent selective ER degraders and/or new targeted biotherapies are needed to overcome the endocrineresistant phenotype of ESR1 mutant-bearing tumors. In this review, we discuss the mechanisms of resistance and dissemination of ESR1 mutations as well as the detection methods for ESR1 mutation tracking, newly discovered potential therapeutic targets, and the clinical implications and treatment options for treating patients with ESR1 mutant-bearing tumors.

show abstract

Section: Biology Of Esr1 Mutations In Preclinical Studiesmentioning

confidence: 99%

Section: Biology Of Esr1 Mutations In Preclinical Studiesmentioning

confidence: 99%

Section: Implications Of Esr1 Mutations In Metastasis and Tumor Progrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

ESR1 mutations in breast cancer

Dustin

Fuqua

2019

Cancer

194

131

View full text Add to dashboard Cite

show abstract

Estrogen Receptor Modulators

Rosales

Gutgesell

Ratia

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The estrogen receptor (ER) has historically played and continues to play a prominent role in drug discovery as a target for medicinal chemists. The first targeted cancer therapy was directed at ERα and the first clinical drug that is a proteolysis targeting small molecule is also an ER ligand used to treat metastatic breast cancer. The last decade has been described as a renaissance in the medicinal chemistry of endocrine therapy, therefore, this article focuses on design of small molecule ERα ligands for treatment of hormone‐dependent breast cancer. As our understanding of the role of ER in resistance to endocrine therapy increases, further opportunities will be presented for medicinal chemists to design therapeutic agents for metastatic disease. Beyond breast cancer, ER, whether nuclear or extranuclear remains largely unexploited as a target for small molecule drug design, which is partly explained by the complexity of the underlying biology and partly by the cooling influence of the initial Women's Health Initiative outcomes on estrogen replacement therapy. Old and new concepts of ligand binding and signal transduction by ER are presented to stimulate the interests of medicinal chemists; accompanied by a catalogue of newer small molecule ligands reported in the literature and their interactions with ER.

show abstract

Proteomics on malignant pleural effusions reveals ERα loss in metastatic breast cancer associates with SGK1–NDRG1 deregulation

Mayayo‐Peralta,

Debets,

Prekovic

et al. 2023

Molecular Oncology

Self Cite

View full text Add to dashboard Cite

Breast cancer (BCa) is a highly heterogeneous disease, with hormone receptor status being a key factor in patient prognostication and treatment decision‐making. The majority of primary tumours are positive for estrogen receptor alpha (ERα), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one third of patients with ERα‐positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ERα expression after endocrine treatment, known as ERα‐conversion. It remains unclear whether ERα‐converted cancers are biologically similar to bona fide ERα‐negative disease and which signalling cascades compensate for ERα loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ERα loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 breast cancer patients, comparing ERα‐positive, ERα‐converted and ERα‐negative cases. Our data revealed that the loss of ERα‐dependency in this metastatic site leads to only a partial switch to an ERα‐negative molecular phenotype, with preservation of a luminal‐like proteomic landscape. Furthermore, we found evidence for decreased activity of several key kinases, including serum/glucocorticoid regulated kinase 1 (SGK1), in ERα‐converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ERα‐dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.

show abstract

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance

Cited by 123 publications

References 45 publications

ESR1 mutations in breast cancer

ESR1 mutations in breast cancer

Estrogen Receptor Modulators

Proteomics on malignant pleural effusions reveals ERα loss in metastatic breast cancer associates with SGK1–NDRG1 deregulation

Contact Info

Product

Resources

About