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Insulin-Like Growth Factor Binding Protein-3 Expression Is Associated with Growth Stimulation of T47D Human Breast Cancer Cells: The Role of Altered Epidermal Growth Factor Signaling

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Alison J. Butt, Ph.D., Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail: a.butt{at}garvan.org.au.

IGF binding protein (IGFBP)-3 has antiproliferative and proapoptotic effects on the growth of human breast cancer cells in vitro. However, clinical studies suggest that high levels of IGFBP-3 in breast tumor tissue are associated with large, highly proliferative tumors. In this study, we examined the effects of stable transfection with human IGFBP-3 cDNA on the growth of T47D human breast cancer cells in vitro and in vivo. Expression of IGFBP-3 initially inhibited the growth of T47D in vitro but was associated with enhanced growth in vivo. Furthermore, IGFBP-3-expressing cells in vitro became growth stimulated at higher passages post transfection, suggesting breast cancer cells may switch their response to IGFBP-3 with increasing tumorigenicity. These stimulatory effects observed in IGFBP-3-expressing cells were associated with an enhanced responsiveness to the proliferative effects of epidermal growth factor (EGF). When EGF receptor (EGFR) kinase activity was blocked using PD153035, high passage IGFBP-3 transfectants were growth inhibited compared with controls treated with inhibitor. These findings suggest that the interaction between IGFBP-3 and the EGFR system is central to whether IGFBP-3 acts as a growth stimulator or inhibitor in breast cancer cells and that therapies targeting EGFR may have increased efficacy in breast tumors expressing high levels of IGFBP-3.

This work was supported by Grants 107242 (to A.J.B. and R.C.B.) and 107244 (to J.L.M. and R.C.B.) from the National Health and Medical Research Council, Australia.

Abbreviations: EGF, Epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; IGFBP, IGF binding protein; PI, phosphatidylinositol; RT, room temperature; SF, serum-free/insulin-free.

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