Effects of endogenous insulin-like growth factor binding protein-3 on cell cycle regulation in breast cancer cells

Abstract

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.

Keywords::

• IGFBP-3
• cell cycle regulation
• migration
• RNA interference
• breast cancer cells

Acknowledgements

We thank Tercica (Brisbane, CA, USA) for providing the IGF-I. This work was supported by the National Health and Medical Research Council, Australia, Grant 302171 (L. J. Schedlich, R. C. Baxter) and a Cancer Institute NSW Research Scholar Award (M. K. O'Han).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.