Involvement of Pin1 induction in epithelial–mesenchymal transition of tamoxifen‐resistant breast cancer cells

Acquisition of resistance to tamoxifen is a critical therapeutic problem in breast cancer patients. Epithelial–mesenchymal transition (EMT), where cells undergo a developmental switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype, is associated with invasion and motility of cancer cells. Here, we found that tamoxifen‐resistant (TAMR)‐MCF‐7 cells had undergone EMT, as evidenced by mesenchymal‐like cell shape, downregulation of basal E‐cadherin expression, and overexpression of N‐cadherin and vimentin, as well as increased Snail transcriptional activity and protein expression. Given the roles of glycogen synthase kinase (GSK)‐3β and nuclear factor (NF)‐κB in Snail‐mediated E‐cadherin deregulation during EMT, we examined the role of these signaling pathways in the EMT of TAMR‐MCF‐7 cells. Both Ser9‐phosphorylated GSK‐3β (inactive form) and NF‐κB reporter activity were increased in TAMR‐MCF‐7 cells, as was activation of the phosphatase and tensin homolog depleted on chromosome ten (PTEN)–phosphoinositide 3 (PI3)‐kinase–Akt pathway. Pin1, a peptidyl‐prolyl isomerase, was overexpressed in TAMR‐MCF‐7 cells, and Snail transcription and the expression of EMT markers could be decreased by Pin1 siRNA treatment. These results imply that Pin1 overexpression in TAMR‐MCF‐7 cells is involved in the EMT process via PTEN–PI3‐kinase–Akt–GSK‐3β and/or GSK‐3β–NF‐κB‐dependent Snail activation, and suggest the potential involvement of Pin1 in EMT during breast cancer development. ( Cancer Sci  2009; 100: 1834–1841)