Abstract
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. We have shown that Pin1, a peptidyl prolyl isomerase, is consistently overexpressed in TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) and plays a key role in the enhanced angiogenic potential of TAMR-MCF-7 cells. In the present study, we focused on signaling pathways for Pin1 up-regulation in TAMR-MCF-7 cells. Relative to MCF-7 cells, Pin1 gene transcription and E2 transcription factor1 (E2F1) expression were enhanced in TAMR-MCF-7 cells. E2F1 siRNA significantly reduced both the protein expression and the promoter transcriptional activity of Pin1. Activities of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and p38 kinase were all higher in TAMR-MCF-7 cells than in control MCF-7 cells and the enhanced Pin1 and E2F1 expression in TAMR-MCF-7 cells was reversed by inhibition of PI3K or p38 kinase. Moreover, the higher production of vascular endothelial growth factor (VEGF) in TAMR-MCF-7 cells was significantly diminished by suppression of PI3K or p38 kinase. These results suggest that Pin1 overexpression and subsequent VEGF production in TAMR-MCF-7 cells are mediated through PI3-kinase or p38 kinase-dependent E2F1 activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Hormonal / pharmacology
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Antineoplastic Agents, Hormonal / therapeutic use
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Blotting, Western
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Breast Neoplasms* / drug therapy
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Breast Neoplasms* / genetics
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Breast Neoplasms* / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm*
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E2F1 Transcription Factor / genetics
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E2F1 Transcription Factor / metabolism*
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Enzyme-Linked Immunosorbent Assay
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Female
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Gene Expression Regulation, Neoplastic*
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Gene Silencing / drug effects
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Genes, Reporter
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Humans
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Luciferases / analysis
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NIMA-Interacting Peptidylprolyl Isomerase
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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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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Signal Transduction
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Tamoxifen / pharmacology*
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Tamoxifen / therapeutic use
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Up-Regulation
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antineoplastic Agents, Hormonal
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E2F1 Transcription Factor
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E2F1 protein, human
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NIMA-Interacting Peptidylprolyl Isomerase
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RNA, Small Interfering
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Tamoxifen
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Luciferases
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Phosphatidylinositol 3-Kinases
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p38 Mitogen-Activated Protein Kinases
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PIN1 protein, human
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Peptidylprolyl Isomerase