Enhancement of vascular endothelial growth factor-mediated angiogenesis in tamoxifen-resistant breast cancer cells: role of Pin1 overexpression.
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 1alpha 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 Pin1 is a potential therapeutic target of excessive angiogenesis in TAM-resistant breast cancer cases.
Kim
Mi Ra
MR
BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, South Korea.
Choi
Hong Seok
HS
Yang
Jin Won
JW
Park
Byung Chul
BC
Kim
Jung-Ae
JA
Kang
Keon Wook
KW
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018808:Transcription Factor AP-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase