Effects of endogenous insulin-like growth factor binding protein-3 on cell cycle regulation in breast cancer cells.
High tissue insulin-like growth factor binding protein-3 (IGFBP-3) expression in breast cancers is associated in some studies with rapid growth and poor outcome. This study examined the effects of endogenous IGFBP-3 in Hs578T breast cancer cells, which are IGF-unresponsive and grow aggressively despite relatively high IGFBP-3 expression. IGFBP-3 downregulation using siRNA was associated with increases in DNA synthesis, the percentage of cells in S phase and viable cell numbers, accompanied by increases in cyclins A and D1, a decrease in p27 expression, and increased phosphorylation of retinoblastoma (Rb) on Ser795. Downregulation of IGFBP-3 inhibited extracellular signal-regulated kinase (ERK) activation and cell migration in a monolayer wound healing assay. These results indicate that endogenous IGFBP-3 is anti-proliferative and pro-migratory in Hs578T cells and that these effects are IGF-independent. Poor outcome in breast tumours expressing high levels of IGFBP-3 may be due to the effects of IGFBP-3 on cell migration rather than cell growth.
O'Han
Michelle K
MK
Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, 2065, Australia.
Baxter
Robert C
RC
Schedlich
Lynette J
LJ
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D034622:RNA Interference
D018972:Insulin-Like Growth Factor Binding Protein 3