E-cadherin promotes cell hyper-proliferation in breast cancer

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. SUMMARY E-cadherin, an extensively studied transmembrane molecule ubiquitously expressed in normal epithelial tissues, promotes and maintains intercellular adhesion. In cancer, the loss of adhesion molecule E-cadherin is associated with onset of invasion via epithelial-to-mesenchymal transition (EMT) process.[1][1] EMT consists of a highly orchestrated cascade of molecular events where epithelial cells switch from a non-motile phenotype to an invasive, migratory phenotype accompanied by a change in cell morphology.[1][1],[2][2] These processes are believed to then trigger metastasis in carcinomas (cancers of epithelial origin). Moreover, the expression of intercellular adhesion molecule E-cadherin (E-cad) is associated with a decrease in cell proliferation in normal cells. Classical experiments in fibroblasts and epithelial cells show that the expression of E-cad not only promotes cell-cell adhesion, but also reduces cell proliferation and onset of apoptosis.[3][3],[4][4] Altogether these results have long supported that E-cad acts as a tumor suppressor gene.[1][1],[2][2] However, despite its role in cell-adhesion the requirement for loss of E-cad in metastasis has recently been re-assessed.[5][5],[6][6],[7][7],[8][8] These investigations focus on E-cad’s role in EMT, even though the relationship between E-cad and proliferation is just as intriguing. While E-cad has been shown to have anit-proliferative effects in normal cells, E-cad also helps maintain a pluripotent and proliferative phenotype in stem cells, and notably is lost during differentiation, a non-proliferative step of stem cell progression.[9][9],[10][10] Yet, despite potentially important implications in our understanding of tumor progression, whether E-cad expression affects growth in cancer cells remains mostly unexplored. Here, utilizing a physiologically relevant 3D in vitro model and multiple in vivo models, we studied the impact of E-cad on cell proliferation at the primary tumor site and proliferation at a secondary site. Remarkably, E-cad upregulates multiple proliferation pathways, including hyper-activation of the ERK cascade within the greater MAPKinase pathway, resulting in a dramatic increase in cell proliferation in vitro and tumor growth in vivo . When the phosphorylation of ERK is blocked utilizing a MEK1/2 inhibitor, PD0325901[11][11], this effect is reversed in vitro and in vivo . Thus, E-cad plays an oncogenic role in tumorigenesis and merits evaluation as a potential new drug target. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: #ref-11