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

Gabriella C Russo; Ashleigh J Crawford; David Clark; Julie Cui; Ryan Carney; Michelle N Karl; Boyang Su; Bartholomew Starich; Tung-Shing Lih; Pratik Kamat; Qiming Zhang; Praful R Nair; Pei-Hsun Wu; Meng-Horng Lee; Hon S Leong; Hui Zhang; Vito W Rebecca; Denis Wirtz

doi:10.1038/s41388-024-03007-2

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

Oncogene. 2024 Mar 20. doi: 10.1038/s41388-024-03007-2. Online ahead of print.

Authors

Gabriella C Russo^{1

2}, Ashleigh J Crawford^{1

2}, David Clark³, Julie Cui¹, Ryan Carney⁴, Michelle N Karl^{1

2}, Boyang Su⁵, Bartholomew Starich^{1

2}, Tung-Shing Lih³, Pratik Kamat^{1

2}, Qiming Zhang¹, Praful R Nair^{1

2}, Pei-Hsun Wu^{1

2}, Meng-Horng Lee¹, Hon S Leong^{5

6}, Hui Zhang³, Vito W Rebecca⁷, Denis Wirtz^{8

9}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.
² Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.
³ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
⁴ Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁶ Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
⁷ Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, MD, 21231, USA.
⁸ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA. wirtz@jhu.edu.
⁹ Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD, 21218, USA. wirtz@jhu.edu.

PMID: 38509231
DOI: 10.1038/s41388-024-03007-2

Abstract

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.

Abstract

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