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

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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.

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Fig. 1: Manipulation of E-cadherin expression impacts proliferation in breast cancer cells.
Fig. 2: E-cadherin promotes hyper-proliferation via the MAPK pathway.
Fig. 3: E-cadherin expression correlates with increased proliferation and activation of MAPK pathway.
Fig. 4: E-cadherin results in larger metastatic burden in two in vivo models via MAPK proliferation pathway.
Fig. 5: Blocking ERK phosphorylation stops hyper-proliferative effect of E-cad.

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD021545 and 10.6019/PXD021545. Please use the following username and password to access the data: Username: reviewer_pxd021545@ebi.ac.uk Password: MYmOhJvc.

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Acknowledgements

We thank all members of the Wirtz Lab for discussions and feedback on this project. We also thank Alan Meeker and Sujayita Roy from the Oncology Tissue Services IHC Core at Johns Hopkins Medical Campus for their assistance with IHC. This work was supported through grants from the National Cancer Institute (U54CA143868, UG3CA275681, and U54CA268083), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR081774), and the National Institute on Aging (U01AG060903) to DW and PHW.

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GCR and DW developed the hypothesis and designed experiments. GCR performed most experiments and data analysis. AJC, JC, RC, MNK, BS, and MHL assisted with the experiments. VWR assisted with proximity ligation assay. DC, TL, HZ performed proteomics experiments, assisted in the analysis, and edited the manuscript. BS and HSL performed CAM experiments, assisted in the analysis, and edited the manuscript. QZ assisted with the Metabric analysis of clinical data. PRN analyzed TCGA invasive breast carcinoma data sets for correlation with E-cad (CDH1) expression. PW assisted with image analysis. GCR and DW wrote the manuscript with input from AJC and VWR.

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Correspondence to Denis Wirtz.

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Russo, G.C., Crawford, A.J., Clark, D. et al. E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer. Oncogene 43, 1445–1462 (2024). https://doi.org/10.1038/s41388-024-03007-2

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