Specific Features of Epithelial-Mesenchymal Transition Induced by Driver Mutations in the PI3K/AKT Signaling Pathway in Breast Epithelial Cells

Abstract: The PI3K/AKT signaling pathway is one of the most critical intracellular pathways, regulating cell proliferation, survival, and migration. Mutations in PI3K/AKT pathway components are frequently associated with progression and metastasis of malignant tumors. The initial stage of metastasis is epithelial-mesenchymal transition (EMT), during which tumor cells acquire the migratory capacity. The data on the impact of PI3K/AKT driver mutations on tumor cell motility are contradictory. We investigated EMT and changes in the motility of breast epithelial cells carrying four driver mutations commonly identified in malignant tumors and affecting different components of the PI3K/AKT pathway. Analysis of cell motility, expression of EMT markers, and morphology of adherens junctions (AJs) revealed that all these mutations induced partial EMT, as E-cadherin expression was preserved in all studied cell lines and cells maintained AJs. Analysis of EMT types induced by different mutations revealed that the increased cell motility did not correlate with the degree of EMT progression toward the mesenchymal phenotype. The greatest increase in the cell migratory capacity was observed for cells carrying the PIK3CA H1047R mutation, which induced the most pronounced mesenchymal phenotype, as well as for PTEN–/– cells, which retained the most epithelial phenotype. Our analysis showed that mutations indirectly affecting the MAPK/ERK pathway and promoting ERK activation have the greatest impact on EMT and cell motility.