Journal
MOLECULAR CANCER THERAPEUTICS
Volume 8, Issue 8, Pages 2163-2171Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-08-1061
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Funding
- MOST/KOSEF Seoul National University [R11-2007-107-01002-0(2008), R01-2007-000-20093-0]
- National Research Foundation of Korea [R01-2007-000-20093-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. Here, we found that TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) produced higher levels of vascular endothelial growth factor (VEGF) than control MCF-7 cells. Molecular analyses using reporter genes and Western blots supported the involvement of c-Jun/activator protein-1 and hypoxia-inducible factor 1 alpha in enhanced VEGF transcription in TAMR-MCF-7 cells. Pin1, a peptidyl prolyl isomerase, was consistently overexpressed in TAMR-MCF-7 cells, and c-Jun/activator protein-1-dependent VEGF transcription in TAMR-MCF-7 cells was almost completely inhibited by Pin1 siRNA and by the Pin1 inhibitor Juglone. Chick chorioallantoic membrane assays confirmed that the increased angiogenic intensity of TAMR-MCF-7 cells was significantly suppressed by Pin1 inhibition. These results show that Pin1 overexpression is closely associated with VEGF-mediated angiogenesis and suggest that Pin 1 is a potential therapeutic target of excessive angiogenesis in TAM-resistant breast cancer cases. [Mol Cancer Ther 2009;8(8):2163-71]
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