Transforming growth factor-beta-induced cell growth inhibition in human breast cancer cells is mediated through insulin-like growth factor-binding protein-3 action.
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.
Oh
Y
Y
Department of Pediatrics, School of Medicine, Oregon Health Sciences University, Portland 97201-3042, USA.
Müller
H L
HL
Ng
L
L
Rosenfeld
R G
RG
D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D013002:Somatomedins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D006131:Growth Inhibitors; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D013002:Somatomedins; D016212:Transforming Growth Factor beta