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)-3beta and nuclear factor (NF)-kappaB 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-3beta (inactive form) and NF-kappaB 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-3beta and/or GSK-3beta-NF-kappaB-dependent Snail activation, and suggest the potential involvement of Pin1 in EMT during breast cancer development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cadherins / genetics
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Cadherins / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm / physiology*
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Epithelial Cells / pathology
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Female
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Gene Expression Regulation, Neoplastic / physiology*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Immunoblotting
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Mesoderm / pathology
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NF-kappa B / genetics
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NF-kappa B / metabolism
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NIMA-Interacting Peptidylprolyl Isomerase
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Neoplasm Invasiveness / pathology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Peptidylprolyl Isomerase / genetics
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Peptidylprolyl Isomerase / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering
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Selective Estrogen Receptor Modulators / pharmacology
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Signal Transduction / physiology*
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Snail Family Transcription Factors
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Tamoxifen / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Cadherins
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NF-kappa B
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NIMA-Interacting Peptidylprolyl Isomerase
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RNA, Small Interfering
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Selective Estrogen Receptor Modulators
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Snail Family Transcription Factors
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Transcription Factors
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Tamoxifen
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Phosphatidylinositol 3-Kinases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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PTEN Phosphohydrolase
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PIN1 protein, human
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Peptidylprolyl Isomerase