ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges

Herzog, Sarah K.; Fuqua, Suzanne A.W.

doi:10.1038/s41416-021-01564-x

Cited by 65 publications

(42 citation statements)

References 79 publications

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“…For example, ASNS has a strong correlation in cancers such as ovarian cancer (Zeng et al, 2019), leukemia (Watanabe et al, 2020) and B-cell lymphoma (Grima-Reyes et al, 2022). AURKA and ESR1 confer cellular drug resistance when overexpressed in ER-positive BC (Wander et al, 2020;Herzog and Fuqua, 2022). This proves that the key genes obtained from our screen are very reliable and may become key genes for BC development and drug-resistant BC.…”

Section: Discussionsupporting

confidence: 55%

Tamoxifen resistance-related ceRNA network for breast cancer

Qiao

Lei²,

Zhang³

et al. 2022

Front. Cell Dev. Biol.

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Background: Tamoxifen (TMX) is one of the most widely used drugs to treat breast cancer (BC). However, acquired drug resistance is still a major obstacle to its application, rendering it crucial to explore the mechanisms of TMX resistance in BC. This aims of this study were to identify the mechanisms of TMX resistance and construct ceRNA regulatory networks in breast cancer.Methods: GEO2R was used to screen for differentially expressed mRNAs (DEmRNAs) leading to drug resistance in BC cells. MiRTarbase and miRNet were used to predict miRNAs and lncRNAs upstream, and the competing endogenous RNA (ceRNA) regulatory network of BC cell resistance was constructed by starBase. We used the Kaplan–Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the expression and prognostic differences of genes in the ceRNA network with core axis, and qRT-PCR was used to further verify the above conclusions.Results: We found that 21 DEmRNAs were upregulated and 43 DEmRNA downregulated in drug-resistant BC cells. DEmRNAs were noticeably enriched in pathways relevant to cancer. We then constructed a protein-protein interaction (PPI) network based on the STRING database and defined 10 top-ranked hub genes among the upregulated and downregulated DEmRNAs. The 20 DEmRNAs were predicted to obtain 113 upstream miRNAs and 501 lncRNAs. Among them, 7 mRNAs, 22 lncRNAs, and 11 miRNAs were used to structure the ceRNA regulatory network of drug resistance in BC cells. 4 mRNAs, 4 lncRNAs, and 3 miRNAs were detected by GEPIA and the Kaplan–Meier plotter to be significantly associated with BC expression and prognosis. The differential expression of the genes in BC cells was confirmed by qRT-PCR.Conclusion: The ceRNA regulatory network of TMX-resistant BC was successfully constructed and confirmed. This will provide an important resource for finding therapeutic targets for TMX resistance, where the discovery of candidate conventional mechanisms can aid clinical decision-making. In addition, this resource will help discover the mechanisms behind this type of resistance.

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Section: Discussionsupporting

confidence: 55%

Tamoxifen resistance-related ceRNA network for breast cancer

Qiao

Lei²,

Zhang³

et al. 2022

Front. Cell Dev. Biol.

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“…Activating mutations in the gene encoding the ER (ESR1) have been identified in the context of metastatic breast cancer previously treated with tamoxifen and aromatase inhibitors (Turner et al, 2020;Zundelevich et al, 2020). Mutations in the ER are associated with reduced progression free survival and overall survival (Turner et al, 2020;Zundelevich et al, 2020) as well as resistance to the HR+ breast cancer standard of care (Herzog and Fuqua, 2021;Liang et al, 2022). Interestingly, it was recently demonstrated that tumors harbouring mutations in the ER had elevated levels of inflammatory cytokines S100A8 and S100A9, T regs and PDL1 positive macrophages in addition to expression of the immunosuppressive cytokine, chitinase-3-like 1 (CHI3L1) (Zhao et al, 2020b;Williams et al, 2021;Li et al, 2022).…”

Section: Targeting Hormone Receptor Positive Breast Cancer-an Immune ...mentioning

confidence: 99%

“…Overall, this data contends that while ER mutations promote therapeutic resistance to the traditional standard of care, the switch to an immune hot microenvironment may be associated with immune vulnerabilities. Several clinical trials assessing next-generation, selective estrogen receptor modulators or degraders are currently in progress to identify ones that have a positive clinical impact on patients harbouring mutant ER tumors/metastases [summarized in (Herzog and Fuqua, 2021)].…”

Section: Targeting Hormone Receptor Positive Breast Cancer-an Immune ...mentioning

confidence: 99%

Tailoring therapies to counter the divergent immune landscapes of breast cancer

Attalla

Taifour²,

Muller³

2023

Front. Cell Dev. Biol.

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Breast cancer remains a significant clinical concern affecting millions of women worldwide. Immunotherapy is a rapidly growing drug class that has revolutionized cancer treatment but remains marginally successful in breast cancer. The success of immunotherapy is dependent on the baseline immune responses as well as removing the brakes off pre-existing anti-tumor immunity. In this review, we summarize the different types of immune microenvironment observed in breast cancer as well as provide approaches to target these different immune subtypes. Such approaches have demonstrated pre-clinical success and are currently under clinical evaluation. The impact of combination of these approaches with already approved chemotherapies and immunotherapies may improve patient outcome and survival.

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“…Missense mutations in oestrogen receptor 1 ( ESR1 ; encoding ERα) most commonly affect residues in the oestrogen ligand-binding domain and adjacent regions, decreasing the responsiveness of ER to the ligand and enabling constitutive transcriptional activity [ 44 ]. Mutations in ESR1 are a key mechanism of endocrine therapy resistance reported in approximately 30% (12–54%) of HR + metastatic breast cancer patients [ 44 ]. ESR1 mutations occur at a higher frequency in metastatic compared with primary breast tumors, implicating them as a cause of treatment failure.…”

Section: Hormone Receptor-positive Endocrine-resistant Cell Linesmentioning

confidence: 99%

In vitro breast cancer models for studying mechanisms of resistance to endocrine therapy

Cheng

Leung

Singleton

2022

Exploration of Targeted Anti-Tumor Therapy

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The development of endocrine resistance is a common reason for the failure of endocrine therapies in hormone receptor-positive breast cancer. This review provides an overview of the different types of in vitro models that have been developed as tools for studying endocrine resistance. In vitro models include cell lines that have been rendered endocrine-resistant by ex vivo treatment; cell lines with de novo resistance mechanisms, including genetic alterations; three-dimensional (3D) spheroid, co-culture, and mammosphere techniques; and patient-derived organoid models. In each case, the key discoveries, different analysis strategies that are suitable, and strengths and weaknesses are discussed. Certain recently developed methodologies that can be used to further characterize the biological changes involved in endocrine resistance are then emphasized, along with a commentary on the types of research outcomes that using these techniques can support. Finally, a discussion anticipates how these recent developments will shape future trends in the field. We hope this overview will serve as a useful resource for investigators that are interested in understanding and testing hypotheses related to mechanisms of endocrine therapy resistance.

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ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges

Cited by 65 publications

References 79 publications

Tamoxifen resistance-related ceRNA network for breast cancer

Tamoxifen resistance-related ceRNA network for breast cancer

Tailoring therapies to counter the divergent immune landscapes of breast cancer

In vitro breast cancer models for studying mechanisms of resistance to endocrine therapy

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