E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer.

Autor: Russo GC; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Crawford AJ; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Clark D; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA., Cui J; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Carney R; Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Karl MN; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Su B; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Starich B; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Lih TS; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA., Kamat P; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Zhang Q; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Nair PR; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Wu PH; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Lee MH; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA., Leong HS; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada., Zhang H; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA., Rebecca VW; Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, MD, 21231, USA., Wirtz D; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA. wirtz@jhu.edu.; Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA. wirtz@jhu.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 May; Vol. 43 (19), pp. 1445-1462. Date of Electronic Publication: 2024 Mar 20.
DOI: 10.1038/s41388-024-03007-2
Abstrakt: The loss of intercellular adhesion molecule E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), during which tumor cells transition into an invasive phenotype. Accordingly, E-cadherin has long been considered a tumor suppressor gene; however, E-cadherin expression is paradoxically correlated with breast cancer survival rates. Using novel multi-compartment organoids and multiple in vivo models, we show that E-cadherin promotes a hyper-proliferative phenotype in breast cancer cells via interaction with the transmembrane receptor EGFR. The E-cad and EGFR interaction results in activation of the MEK/ERK signaling pathway, leading to a significant increase in proliferation via activation of transcription factors, including c-Fos. Pharmacological inhibition of MEK activity in E-cadherin positive breast cancer significantly decreases both tumor growth and macro-metastasis in vivo. This work provides evidence for a novel role of E-cadherin in breast tumor progression and identifies a new target to treat hyper-proliferative E-cadherin-positive breast tumors, thus providing the foundation to utilize E-cadherin as a biomarker for specific therapeutic success.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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