ArticleProceedings of the National Academy of Sciences of the United States of America2022
14-3-3τ drives estrogen receptor loss via ERα36 induction and GATA3 inhibition in breast cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 8 citations in OpenAlex.
- Integrative pipeline to profile and target endocrine therapy-insensitive cell populations in ER+ breast cancer.bioRxiv : the preprint server for biology · 2026Article
- Nucleic sexual hormone receptor signaling pathways in breast cancer: function regulation, crosstalk, and therapeutic implications.NPJ precision oncology · 2026Review
- The Importance of 14-3-3 Proteins in Colorectal Cancer Regulation: Mechanisms of Function and Clinical Opportunities.BioMed research international · 2026Review
- More than alternative estrogen receptors: the emerging role of GPER-1 and ERα36 in breast cancer.Exploration of targeted anti-tumor therapy · 2026Review
- Multidimensional roles and clinical significance of GATA3 in breast cancer.Frontiers in cell and developmental biology · 2026Review
- Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression.The FEBS journal · 2025Review
- Dynamic methylation and expression of alternative promoters for oestrogen receptor alpha in cell line models of fulvestrant resistance.Molecular oncology · 2025Article
- Review
- YWHAG promotes colorectal cancer progression by regulating the CTTN-Wnt/β-catenin signaling axis.Medical oncology (Northwood, London, England) · 2024Article
- Arnicolide C Suppresses Tumor Progression by Targeting 14-3-3θ in Breast Cancer.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Super-enhanced MARCO variant drives triple-negative breast cancer progression.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
About one-fourth of recurrent estrogen receptor-positive (ER+) breast cancers lose ER expression, leading to endocrine therapy failure. However, the mechanisms underlying ER loss remain to be fully explored. We now show that 14-3-3τ, up-regulated in ∼60% of breast cancer, drives the conversion of ER+ to ER- and epithelial-to-mesenchymal transition (EMT). We identify ERα36, an isoform of ERα66, as a downstream effector of 14-3-3τ. Overexpression of 14-3-3τ induces ERα36 in xenografts and tumor spheroids. The regulation is further supported by a positive correlation between ERα36 and 14-3-3τ expression in human breast cancers. ERα36 can antagonize ERα66 and inhibit ERα66 expression. Isoform-specific depletion of ERα36 blocks the ER conversion and EMT induced by 14-3-3τ overexpression in tumor spheroids, thus establishing ERα36 as a key mediator in 14-3-3τ-driven ER loss and EMT. ERα36 promoter is repressed by GATA3, which can be phosphorylated by AKT at consensus binding sites for 14-3-3. Upon AKT activation, 14-3-3τ binds phosphorylated GATA3 and facilitates the degradation of GATA3 causing GATA3 to lose transcriptional control over its target genes ERα66 and ERα36. We also demonstrate a role for the collaboration between 14-3-3τ and AKT in ERα36 induction and endocrine therapy resistance by three-dimensional spheroid and tamoxifen treatment models in MCF7 and T47D ER+ breast cancer cells. Thus, the 14-3-3τ-ERα36 regulation provides a previously unrecognized mechanism for ER loss and endocrine therapy failure.
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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 Socratic graph.