The loss of the intercellular adhesion molecule E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), which promotes a transition of cancer cells to a migratory and invasive phenotype. E-cadherin is associated with a decrease in cell proliferation in normal cells. Here, using physiologically relevant 3D in vitro models, we find that E-cadherin induces hyper-proliferation in breast cancer cells through activation of the Raf/MEK/ERK signaling pathway. These results were validated and consistent across multiple in vivo models of primary tumor growth and metastatic outgrowth. E-cadherin expression dramatically increases tumor growth and, without affecting the ability of cells to extravasate and colonize the lung, significantly increases macrometastasis formation via cell proliferation at the distant site. Pharmacological inhibition of MEK1/2, blocking phosphorylation of ERK in E-cadherin-expressing cells, significantly depresses both tumor growth and macrometastasis. This work suggests a novel role of E-cadherin in tumor progression and identifies a potential new target to treat hyper-proliferative breast tumors.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Pharmacology, Toxicology and Pharmaceutics(all)