ArticleOncogenesis2013
Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells.
Article in Oncogenesis, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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
42 citing papers in PubMed, 61 citations in OpenAlex.
- Notch receptors in breast cancer: context-dependent roles and therapeutic targeting.Cell communication and signaling : CCS · 2026Review
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation ofJournal of thoracic disease · 2024Article
- The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer.Cancers · 2023Article
- Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response.Biology · 2023Review
- Signaling pathways in the regulation of cancer stem cells and associated targeted therapy.MedComm · 2022Review
- A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC).Clinical breast cancer · 2022Article
- Yuanhuacin and Related Anti-Inflammatory and Anticancer Daphnane Diterpenes from Genkwa Flos-An Overview.Biomolecules · 2022Review
- The complexities of PKCα signaling in cancer.Advances in biological regulation · 2021Review
- Cancer stem cells: Culprits in endocrine resistance and racial disparities in breast cancer outcomes.Cancer letters · 2021Article
- Targeting Notch in oncology: the path forward.Nature reviews. Drug discovery · 2021Review
- Nuclear Mechanisms Involved in Endocrine Resistance.Frontiers in oncology · 2021Review
- Systematic Evaluation for the Influences of the SOX17/Notch Receptor Family Members on Reversing Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells.Frontiers in oncology · 2021Article
- Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives.Cancer management and research · 2021Review
- Notch Signalling in Breast Development and Cancer.Frontiers in cell and developmental biology · 2021Review
- The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance.Genes & development · 2020Review
- Epithelial-Mesenchymal Transition Programs and Cancer Stem Cell Phenotypes: Mediators of Breast Cancer Therapy Resistance.Molecular cancer research : MCR · 2020Review
- Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives.Cells · 2020Review
- Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update.Nature reviews. Clinical oncology · 2020Review
- Notch Signaling Pathway and Endocrine Resistance in Breast Cancer.Frontiers in pharmacology · 2020Review
Corrections and comments
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Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Notch pathway is functionally important in breast cancer. Notch-1 has been reported to maintain an estrogen-independent phenotype in estrogen receptor α (ERα)+ breast cancer cells. Notch-4 expression correlates with Ki67. Notch-4 also plays a key role in breast cancer stem-like cells. Estrogen-independent breast cancer cell lines have higher Notch activity than estrogen-dependent lines. Protein kinase Cα (PKCα) overexpression is common in endocrine-resistant breast cancers and promotes tamoxifen (TAM)-resistant growth in breast cancer cell lines. We tested whether PKCα overexpression affects Notch activity and whether Notch signaling contributes to endocrine resistance in PKCα-overexpressing breast cancer cells.Analysis of published microarray data from ERα+ breast carcinomas shows that PKCα expression correlates strongly with Notch-4. Real-time reverse transcription PCR and immunohistochemistry on archival specimens confirmed this finding. In a PKCα-overexpressing, TAM-resistant T47D model, PKCα selectively increases Notch-4, but not Notch-1, expression in vitro and in vivo. This effect is mediated by activator protein-1 (AP-1) occupancy of the Notch-4 promoter. Notch-4 knockdown inhibits estrogen-independent growth of PKCα-overexpressing T47D cells, whereas Notch-4IC expression stimulates it. Gene expression profiling shows that multiple genes and pathways associated with endocrine resistance are induced in Notch-4IC- and PKCα-expressing T47D cells. In PKCα-overexpressing T47D xenografts, an orally active γ-secretase inhibitor at clinically relevant doses significantly decreased estrogen-independent tumor growth, alone and in combination with TAM. In conclusion, PKCα overexpression induces Notch-4 through AP-1. Notch-4 promotes estrogen-independent, TAM-resistant growth and activates multiple pathways connected with endocrine resistance and chemoresistance. Notch inhibitors should be clinically evaluated in PKCα- and Notch-4-overexpressing, endocrine-resistant breast cancers.
Identifiers
What OpenQuestion holds
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.