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

Abstract

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)

Multidrug Resistence and Breast Cancer

“…These results were confirmed in other types of tumors like gemcitabine-resistant pancreatic cancer cells, oxaliplatin-resistant colorectal cancer cells, lapatinib-resistant breast cancer [120]. In addition, tamoxifen-resistant breast cancer cells undergone EMT with altered -catenin phosphorylation [128]. It has been indicated that mesenchymal-like cancers might be more sensitive to DNA damaging agents such as doxorubicin, whereas epithelial-like cancers are more sensitive to targeted therapies, such as EGFR and HER2 antagonists [129].That may be the reason why mesenchymal-like, basal breast cancers are initially more sensitive to chemotherapy than epithelial-like luminal breast cancers [130].…”

PI3-Kinase/p38 Kinase-Dependent E2F1 Activation Is Critical for Pin1 Induction in Tamoxifen-Resistant Breast Cancer Cells

“…We showed that the Pin1 protein level was consistently increased in TAMR-MCF-7 cells compared to control MCF-7 cells (Kim et al, 2009a;2009b) (Fig. 1A).…”

“…Unfortunately, resistance to hormonal therapy is a major clinical problem -most cancer cells can utilize alternative mechanisms for growth and survival after initiation of first-line endocrine therapy (Ali et al, 2002). A series of our studies revealed that both VEGF-mediated angiogenesis and snail-dependent epithelial mesenchymal transitions were stimulated in TAMresistant breast cancer cells, and Pin1 overexpression in this cell type is a critical event for both processes (Kim et al, 2008;2009a;2009b). In the present study, we demonstrated that Pin1 overexpression in TAMR-MCF-7 cells was dependent on transcriptional activation of the Pin1 gene.…”

“…We previously established TAM-resistant breast cancer cells using an ER-positive MCF-7 cell line (TAMR-MCF-7 cells) by long-term culture of MCF-7 cells in hormone-free culture medium that contained 4-hydroxytamoxifen (Choi et al, 2007). A series of our studies revealed that Pin1 was highly expressed in TAMR-MCF-7 cells and that it was required for both enhanced vascular endothelial growth factor (VEGF)-mediated angiogenesis and the Snail-dependent epithelial mesenchymal transition in the cell type (Kim et al, 2009a;2009b). These results suggested that Pin1 is a potential therapeutic target for the treatment of TAM-resistant breast cancer.…”

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

“…Pin1 siRNA treatment resulted in decreased Snail transcription and the expression of EMT markers. It was inferred that pin1 might take part in EMT by affecting pTEN expression and the subsequent pI3-kinase-Akt-dependent GSK-3β inactivation (62). Axl is a transmembrane tyrosine kinase receptor, activated by either its ligand-growth arrest specific 6 or extracellular domain-mediated dimerization or cross-talk with human EgFR2.…”