title: PI3-kinase/p38 kinase-dependent E2F1 activation is critical for Pin1 induction in tamoxifen-resistant breast cancer cells.
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.
authors.affiliation: College of Pharmacy, Chonnam National University, Gwangju, 500-757, Korea.
authors.forename: Kwang Youl
authors.initials: KY
authors.lastname: Lee
authors.forename: Jeong Woon
authors.initials: JW
authors.lastname: Lee
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Nam
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Shim
authors.forename: Youngsup
authors.initials: Y
authors.lastname: Song
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000032:analysis; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase