Therapeutic strategies to induce ERα in luminal breast cancer to enhance tamoxifen efficacy

Esakov, Emily; Hale, James S.; Richards, Elliott G.; Torre-Healy, Luke A.; Gullapalli, Keerthi; Trivedi, Div; Chumakova, Anastasia; Wessely, Oliver; Jensen, Jan; Lathia, Justin D.; Reizes, Ofer

doi:10.1530/erc-19-0042

Cited by 4 publications

(7 citation statements)

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“…To establish a ESR1-mediated miRNA-mRNA regulatory network in ERα positive breast cancer, we searched for the potential datasets in the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/). Only datasets met the following criteria were first included: (1) these data should be derived from tumor tissues of patients with ERα positive breast cancer; (2) included datasets should contain miRNA and mRNA transcriptome data. Then, the abstracts and corresponding information of the datasets of interest were further evaluated.…”

Section: Microarray Expression Profilingmentioning

confidence: 99%

“…Breast cancer is the most common type of cancer and the second prevalent cause of cancer-associated deaths in women worldwide (1). In the United States, an estimate of 252,710 women will be diagnosed with breast cancer every year, with approximately 41,070 breast cancer-associated deaths (2). As the complexity of breast cancer, there are more than 20 various histological subtypes and at least four distinct molecular subtypes (3,4).…”

Section: Introductionmentioning

confidence: 99%

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microRNA-Dependent Modulation of Genes Contributes to ESR1's Effect on ERα Positive Breast Cancer

2020

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Background: Dysregulation of ESR1 accounts for endocrine therapy resistance and metastasis of ERα positive breast cancer. However, the underlying molecular mechanism of ESR1 in ERα positive breast cancer remains insufficiency. Notably, to date, a comprehensive miRNA-mRNA regulatory network involved in modulation of ESR1 in development and progression of ERα positive breast cancer is still not established. Methods: Microarray miRNA and mRNA expression profiling from GEO database were used to obtained significant DE-miRNAs and DE-mRNAs in ERα positive breast cancer. Functional enrichment analysis was conducted by Enrichr database. STRING database was utilized to construct protein-protein interaction network, after which hub genes were identified through Cytoscape. Kaplan-Meier plotter was introduced to perform survival analysis. The relationship between ESR1-miRNA or miRNA-target gene pairs were experimentally validated. Results: 74 DE-miRNAs, including 19 upregulated and 55 downregulated miRNAs, and 830 DE-mRNAs, including 359 upregulated and 471 downregulated mRNAs, in ERα positive breast cancer were identified. Potential DE-mRNAs were statistically enriched in several cancer-associated pathways, such as cell cycle and pathway in cancer. Fifty-one hub genes with node degree more than 10 were screened. Twenty-seven of 51 hub genes had significant prognostic values in ERα positive breast cancer. Based on the 27 hub genes, a miRNA-hub gene network, containing 26 miRNAs, was established. Seven of 26 miRNAs were found to possess prognostic predictive roles for patients with ERα positive breast cancer by combination of TCGA and METABRIC data. Intriguingly, ESR1 positively correlated and regulated the 7 miRNAs and the 7 miRNAs inversely correlated and modulated their corresponding downstream targets in MCF-7 and T47D cells, supporting the accuracy of in silico analysis. The relationship between ESR1-miRNA, miRNA-mRNA, or ESR1-mRNA pairs was validated in clinical ERα positive breast cancer. Conclusions: In total, the current findings from this work add substantially to the understanding of ESR1's molecular regulatory mechanism in ERα positive breast cancer.

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Section: Microarray Expression Profilingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

microRNA-Dependent Modulation of Genes Contributes to ESR1's Effect on ERα Positive Breast Cancer

2020

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“…Genome-based profiling analysis showed that breast cancer can be classified into four molecular subtypes: luminal A, luminal B, HER2 and basal-like [2]. Among the subtypes, luminal A and B account for approximately two-thirds of cases and could benefit from endocrine therapy [3]. Selective estrogen receptor modulators (SERMs) have become the standard treatment for ER alpha-positive patients [4].…”

Section: Introductionmentioning

confidence: 99%

TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression

et al. 2022

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Background Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. Methods TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT–PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT–PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. Results In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. Conclusion Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Graphical abstract

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“…Cancer is initiated when healthy cells grow beyond control to form a mass known as a tumor. Breast cancer, which affects both humans and other mammals, can take place in the inner lining of milk ducts (ductal carcinomas), or the lobules of the breast (lobular carcinomas) [1]. The most prevalent type of breast cancer is the hormone receptor-positive luminal breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Mathematical model for the estrogen paradox in breast cancer treatment

Ouifki

Oke

2022

J. Math. Biol.

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Estrogen is known to stimulate the growth of breast cancer, but is also effective in treating the disease. This is referred to as the "estrogen paradox". Furthermore, short-term treatment with estrogen can successfully eliminate breast cancer, whereas long-term treatment can cause cancer recurrence. Studies highlighted clinical correlations between estrogen and the protein p53 which plays a pivotal role in breast cancer suppression. We sought to investigate how the interplay between estrogen and p53 impacts the dynamics of breast cancer, and further explore if this could be a plausible explanation for the estrogen paradox and the paradoxical tumor recurrence that results from prolonged treatment with estrogen.For this, we propose a novel ODE based mathematical model that accounts for dormant and active cancer cells, along with the estrogen hormone and the p53 protein. We analyze the model's global stability behavior using the Poincaré-Bendixson theorem and results from differential inequalities. We also perform a bifurcation analysis and carry out numerical simulations that elucidate the roles of estrogen and p53 in the estrogen paradox and its long term estrogen paradoxical effect.The mathematical and numerical analyses suggest that the apparent paradoxical role of estrogen could be the result of an interplay between estrogen and p53, and provide explicit conditions under which the paradoxical effect of long-term treatment may be prevented.

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Therapeutic strategies to induce ERα in luminal breast cancer to enhance tamoxifen efficacy

Cited by 4 publications

References 20 publications

microRNA-Dependent Modulation of Genes Contributes to ESR1's Effect on ERα Positive Breast Cancer

microRNA-Dependent Modulation of Genes Contributes to ESR1's Effect on ERα Positive Breast Cancer

TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression

Mathematical model for the estrogen paradox in breast cancer treatment

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