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Transforming growth factor-beta-induced cell growth inhibition in human breast cancer cells is mediated through
Y Oh1, H L Müller, L Ng
1Department of Pediatrics, School of Medicine, Oregon Health Sciences University, Portland 97201-3042, USA.
Abstract:
Most estrogen receptor-negative breast cancer cells, including Hs578T cells, express mRNAs encoding insulin-like growth factor-binding protein (IGFBP)-3, as well as transforming growth factor (TGF)-beta receptors. Our previous studies (Oh, Y., Muller, H. L., Lamson, G., and Rosenfeld, R. G. (1993) J. Biol. Chem. 268, 14964-14971; Oh, Y., Muller, H. L., Pham, H. M., and Rosenfeld, R. G. (1993) J. Biol. Chem. 268, 26045-26048) have demonstrated a significant inhibitory effect of exogenous IGFBP-3 on Hs578T cell growth and existence of IGFBP-3-specific receptors that may mediate those direct inhibitory effect of IGFBP-3. TGF-beta is also a potent growth inhibitor in human breast cancer cells in vitro and regulates IGFBP-3 production in different cell systems, suggesting that IGFBP-3 is a major anti-proliferative factor and a key element for TGF-beta-induced growth inhibition in human breast cancer cells. In support of this hypothesis, we have demonstrated using Hs578T cells that: 1) TGF-beta stimulates IGFBP-3 gene expression and production prior to its inhibition of cell growth, 2) treatment with an IGFBP-3 antisense oligodeoxynucleotide selectively inhibits TGF-beta-induced IGFBP-3 synthesis and cell growth inhibition, and 3) treatment with IGF-II and IGF-II analogs diminish TGF-beta effects by blocking TGF-beta-induced binding of IGFBP-3 to the cell surface. These findings suggest that IGFBP-3 is a major anti-proliferative factor and a key element in TGF-beta-induced growth inhibition in human breast cancer cells.
Insights
Transforming growth factor-beta (TGF-beta) inhibits breast cancer cell growth by increasing insulin-like growth factor-binding protein-3 (IGFBP-3). This study confirms IGFBP-3 as a key anti-proliferative factor in TGF-beta signaling.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Estrogen receptor-negative breast cancer cells, such as Hs578T, express insulin-like growth factor-binding protein (IGFBP)-3 and transforming growth factor (TGF)-beta receptors.
- Previous research demonstrated exogenous IGFBP-3 inhibits Hs578T cell growth, mediated by specific IGFBP-3 receptors.
- TGF-beta is a known potent inhibitor of human breast cancer cell growth in vitro and influences IGFBP-3 production.
Purpose of the Study:
- To investigate the role of IGFBP-3 as a mediator of TGF-beta-induced growth inhibition in human breast cancer cells.
- To confirm IGFBP-3 as a major anti-proliferative factor in this context.
Main Methods:
- Hs578T cells were used to study the effects of TGF-beta on IGFBP-3 gene expression and production.
- IGFBP-3 antisense oligodeoxynucleotide was employed to assess its impact on TGF-beta-induced IGFBP-3 synthesis and cell growth inhibition.
- Insulin-like growth factor (IGF)-II and its analogs were used to evaluate their effect on TGF-beta-induced IGFBP-3 binding to the cell surface.
Main Results:
- TGF-beta treatment stimulated IGFBP-3 gene expression and production preceding growth inhibition in Hs578T cells.
- IGFBP-3 antisense oligodeoxynucleotide selectively blocked TGF-beta-induced IGFBP-3 synthesis and subsequent cell growth inhibition.
- IGF-II and its analogs interfered with TGF-beta effects by inhibiting TGF-beta-induced IGFBP-3 cell surface binding.
Conclusions:
- IGFBP-3 functions as a significant anti-proliferative factor in human breast cancer cells.
- IGFBP-3 is a critical component of the mechanism underlying TGF-beta-induced growth inhibition in breast cancer.