ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Toy, Weiyi; Shen, Yang; Won, Helen; Green, Bradley; Sakr, Rita A.; Will, Marie; Li, Zhiqiang; Gala, Kinisha; Fanning, Sean W.; King, Tari A.; Hudis, Clifford A.; Chen, David; Taran, Tetiana; Hortobágyi, Gabriel N.; Greene, Geoffrey L.; Berger, Michael F.; Baselga, José; Chandarlapaty, Sarat

doi:10.1038/ng.2822

Cited by 1,019 publications

(1,137 citation statements)

References 36 publications

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“…Resistance to endocrine therapies is a major issue in recurrent ER+ HBC patients (De Marchi et al ., 2016). Several mechanisms have been connected to endocrine resistance, such as mutation in the ligand‐binding domain of the ER (Toy et al ., 2013), enhanced growth factor signaling, altered DNA methylation of specific genes (Graff et al ., 1995; Widschwendter and Jones, 2002), or the dysregulation of metabolic pathways (Wang et al ., 2016). In our study, we discovered a novel mechanism demonstrating that Tam decreases Brf1 expression and Pol III gene transcription (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

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Section: Discussionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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“…Constitutive mutants demonstrate increased levels of Ser118 phosphorylation, resistance to HSP90 inhibitor-induced degradation, enhanced recruitment of NCOA family coactivators and/or increased ligand-independent tumor growth in xenograft models compared with wt ERα (Merenbakh-Lamin et al . 2013, Toy et al . 2013, Fanning et al .…”

Section: Impact Of Erα Mutations Found In Endocrine Treatment-resistamentioning

confidence: 99%

“…Accordingly, higher doses of 4-hydroxytamoxifen and ICI 182,780 were required to inhibit the activity of mutant ERα to levels comparable with those observed with the wt ERα; this may lead to resistance to treatment with AEs in the clinic if concentrations high enough to suppress activity of the mutants cannot be achieved (Merenbakh-Lamin et al . 2013, Toy et al . 2013, Jeselsohn et al .…”

Section: Impact Of Erα Mutations Found In Endocrine Treatment-resistamentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…FGFR1 amplification as well as a mutation in ER indicated poor response to tamoxifen 37, 38. Additionally, preclinical studies indicate that the presence of this ER mutation leads to ligand independent activation and is hence likely to render poor response to aromatase inhibitors 39, 40.…”

Section: Resultsmentioning

confidence: 99%

StrandAdvantage test for early‐line and advanced‐stage treatment decisions in solid tumors

et al. 2017

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Comprehensive genetic profiling of tumors using next‐generation sequencing (NGS) is gaining acceptance for guiding treatment decisions in cancer care. We designed a cancer profiling test combining both deep sequencing and immunohistochemistry (IHC) of relevant cancer targets to aid therapy choices in both standard‐of‐care (SOC) and advanced‐stage treatments for solid tumors. The SOC report is provided in a short turnaround time for four tumors, namely lung, breast, colon, and melanoma, followed by an investigational report. For other tumor types, an investigational report is provided. The NGS assay reports single‐nucleotide variants (SNVs), copy number variations (CNVs), and translocations in 152 cancer‐related genes. The tissue‐specific IHC tests include routine and less common markers associated with drugs used in SOC settings. We describe the standardization, validation, and clinical utility of the StrandAdvantage test (SA test) using more than 250 solid tumor formalin‐fixed paraffin‐embedded (FFPE) samples and control cell line samples. The NGS test showed high reproducibility and accuracy of >99%. The test provided relevant clinical information for SOC treatment as well as more information related to investigational options and clinical trials for >95% of advanced‐stage patients. In conclusion, the SA test comprising a robust and accurate NGS assay combined with clinically relevant IHC tests can detect somatic changes of clinical significance for strategic cancer management in all the stages.

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ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Cited by 1,019 publications

References 36 publications

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Antiestrogens: structure-activity relationships and use in breast cancer treatment

StrandAdvantage test for early‐line and advanced‐stage treatment decisions in solid tumors

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