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)-3b 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-3b (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 ( B reast cancer is the most common malignancy in Western women. Hormone-dependent control of growth is a characteristic of breast cancer. Ovarian steroid hormones, including estrogen, are essential for both mammary gland development and breast carcinoma formation.(1,2) Hence, the administration of anti-estrogens to reduce breast tumor growth has played a key role in the endocrine therapy of breast cancer. Tamoxifen (TAM), a non-steroidal anti-estrogen, is the most widely used anti-estrogen in estrogen receptor-positive breast cancer patients.(3) Despite an initial response to TAM, the majority of patients will ultimately relapse and present with disease progression. Therefore, resistance to TAM is a major challenge in the management of breast cancer patients. (4,5) To mimic this condition, we and others have established an MCF-7-derived TAM-resistant cell line (TAMR-MCF-7 cells) by long-term (>9 months) culture of MCF-7 cells with 4-hydroxytamoxifen. (6,7) Epithelial tumors metastasize by initially invading the adjacent tissues, a process involving the loss of their cell-cell adhesions and the acquisition of migratory capabilities. These processes coincide with phenotype changes associated with epithelialmesenchymal transitions (EMT), similar to those that take place during certain steps of embryonic development. (8) EMT is involved in the efficient invasion and motility of cancer cells, because migration of single cancer cells is elicited by using either mesenchymal or amoeboid phenotypes.(9,10) The invasive and metastatic phenotype is associated with downregulation of E-cadherin expression.(11) Several mechanisms have been implicated in the regulation of E-cadherin expression during tumor progression, including genetic, epigenetic, and transcriptional changes. (12,13)
