Insulin-like growth factor binding protein-2 alters the sensitivity of breast cancer cells to chemotherapy

Introduction

Insulin-like growth factor binding protein-2 (IGFBP-2) is often elevated in breast tumours and the presence of IGFBP-2 has been shown to correlate with malignancy. Previously we have shown that IGFBP-2 reduces PTEN abundance [1] and thus helps to maintain the activity of the phosphoinositide 3-kinase signalling cascade, a key mitogenic and survival pathway.

Objective

We therefore investigated whether IGFBP-2 could act as a survival factor for breast cancer cell lines. Using MCF7 and T47D cells, we tested the ability of exogenous IGFBP-2 to alter apoptosis induced by various chemotherapeutic agents. As both these cell lines produce large amounts of IGFBP-2, we also examined the effect of silencing IGFBP-2 using siRNA.

Results

In MCF7 cells, paclitaxel (50 μM) increased cell death from 9% to 24.5% (P < 0.001). Addition of IGFBP-2 (25 ng/ml) decreased the induced cell death by almost one-half to 17.7% (P = 0.047). 5-Fluorouricil (20 μM) increased cell death of T47D cells by 54% (P = 0.044), which was completely blocked by the addition of IGFBP-2. Conversely, loss of IGFBP-2 enhanced chemotherapy-induced apoptosis in both cell lines compared with a nonsilencing siRNA. We also observed that loss of IGFBP-2 reduced cellular proliferation - the live cell number decreased 73% (P < 0.001) and 33% (P < 0.001) in the MCF7 and T47D cells, respectively. Additionally, in the MCF7 cells, loss of IGFBP-2 alone increased cell death threefold (P < 0.001).

Conclusions

These data show that the production of IGFBP-2 by breast cancer cells enhances their survival and protects them against chemotherapy. Thus in breast tumours the increase in IGFBP-2 production could be a survival mechanism making IGFBP-2 a legitimate target for intervention.