ArticleMolecular and cellular biology2004
Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway.
Article in Molecular and cellular biology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 168 citations in OpenAlex.
- Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14-13/PrE0109).Breast cancer research : BCR · 2024Trial
- PI3K signaling in breast cancer: therapeutic advances versus adaptive resistance.The Journal of clinical investigation · 2026Review
- Effects of short-course preoperative endocrine therapy on tumour morphology and immunohistochemical profile in oestrogen receptor-positive, HER2-negative breast cancer.Histopathology · 2026Article
- Integrated Multiomic Profiling Identifies BRD8/EP400 as a Pivotal Chromatin Module Mediating Anti-HER2 Response in HR+/HER2+ Breast Cancer.Cancer research · 2026Article
- Toward Sustainable Care in HER2-Positive Metastatic Breast Cancer: Emerging Evidence for Treatment De-escalation.Cancer research and treatment · 2026Review
- Molecular mechanisms of RACK1-driven metastasis in pancreatic ductal adenocarcinoma revealed by single-cell RNA sequencing.Discover oncology · 2025Article
- Emerging importance of HER3 in tumorigenesis and cancer therapy.Nature reviews. Clinical oncology · 2025Review
- Transcriptomic analysis of the 12 major human breast cell types reveals mechanisms of cell and tissue function.PLoS biology · 2024Article
- FOXO3a-interacting proteins' involvement in cancer: a review.Molecular biology reports · 2024Review
- Prognosis in HR-positive metastatic breast cancer with HER2-low versus HER2-zero treated with CDK4/6 inhibitor and endocrine therapy: a meta-analysis.Frontiers in oncology · 2024Article
- MicroRNAs as the Critical Regulators of Forkhead Box Protein Family in Pancreatic, Thyroid, and Liver Cancers.Biochemical genetics · 2023Review
- Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers.Nature communications · 2023Article
- Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer.NPJ breast cancer · 2023Review
- The forkhead box O3 (FOXO3): a key player in the regulation of ischemia and reperfusion injury.Cellular and molecular life sciences : CMLS · 2023Review
- Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer.Cancers · 2023Review
- Article
- Review
- CCL23 suppresses liver cancer progression through the CCR1/AKT/ESR1 feedback loop.Cancer science · 2021Article
- Hypoxia promotes pancreatic cancer cell migration, invasion, and epithelial-mesenchymal transition via modulating the FOXO3a/DUSP6/ERK axis.Journal of gastrointestinal oncology · 2021Article
- Article
32 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The expression status of the estrogen receptor alpha (ERalpha) and that of the epidermal growth factor receptor Her-2/neu frequently correlate inversely in breast cancers. While ERalpha-dependent cancers respond to antiestrogen therapy, Her-2/neu-overexpressing cancers typically display resistance to antiestrogens and poor prognosis. In this report we have explored the mechanism linking the loss of expression of ERalpha in breast cancer cells with overexpression of Her-2/neu, which signals constitutively via a phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathway. We identify for the first time the Forkhead box protein FOXO3a (formerly termed FKHRL-1), which is inactivated by Akt, as a key regulator of ERalpha gene transcription. In breast cancer cell lines, expression of ERalpha was correlated with active FOXO3a levels. Ectopic FOXO3a expression induced ERalpha protein levels and promoter activity, while a dominant negative FOXO3a decreased ERalpha levels. By using transient transfection, mobility shift assays, and site-directed mutagenesis, two major functional Forkhead binding sites were identified in the human ERalpha promoter B. A chromatin immunoprecipitation assay confirmed FOXO3a binding at these two sites. Ectopic FOXO3a induced estrogen response element-driven reporter activity and expression of ERalpha target genes. The constitutively activated myristylated Akt reduced ERalpha expression, whereas agents that negatively affect the PI3K/Akt pathway, i.e., wortmannin, celecoxib, and the green tea polyphenol epigallocatechin-3 gallate, induced ERalpha. Thus, FOXO3a represents an important intracellular mediator of ERalpha expression, suggesting possible therapeutic intervention strategies for Her-2/neu-overexpressing refractory breast tumors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.