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SECOND INTERNATIONAL SYMPOSIUM
ON THE ROLE OF SOY
IN PREVENTING AND TREATING CHRONIC DISEASESeptember 15-18, 1996
Brussells, Belgium
POSTER ABSTRACTSGenistein may inhibit the growth of human mammary epithelIal (HME) cell by augmenting transforming growth factor beta (TGFB) signaling.
T.G. Peterson, H. Kim and S. Barnes. Department of Pharmacology and Toxicology.
University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Mechanisms that have been proposed to account for the chemopreventive action of genistein mostly center on inhibition of membrane bound and intracellular protein tyrosine kinases (PTK). However, although genistein inhibits the epidermal growth factor (EGF)stimulated growth of human breast cancer cell lines (Peterson and Barnes, Cell Growth & Differentiation, in press) and normal human mammary epitheilal (HME) cells, it does not inhibit EGF receptor tyrosine autophosphorylation, suggesting that a mechanism other than PTK inhibition is involved. Since genistein inhibits can cycle progression at G1/S, we investigated the role of genistein on the regulation of cellular proteins which block cell growth at the G1/S boundary, such as TGFB. Addition of TGFB (IC502.4ng/ml) or genistein (IC 50 5mM) inhibited the EGF-stimulated growth of HME cells. The growth inhibitory effects of both genistein and TGFB were reversed by the addition of anti - TGFB 1,2,3 or anti-TGFB1 antibodies to the culture medium, suggesting that genistein induced synthesis of TGFB1 was resonsible for the growth inhibition in HME cells. The anti-TGFB antibodies had no effect on the EGF-stimulated growth of untreated HME cells in the abscence of TGFB1 or genistein. SELISA analysis revealed a 4.7 -fold in- crease in the amount of TGFB1secreted into the medium by the HME cells treated with genistein and EGF compared to the amount secreted by cells treated with EGF alone. We conclude that the mechanism of genisteinsís inhibition of the growth of HME cells is based on regulation of TGFB synthesis, either through increased synthesis or decreased degradation, thereby modulating TGFB signailing. Support for this concept comes from clinical studies in which consumption of a soy-based beverage (that includes genistein) has been shown to be effective in the treatment of the human nosebleed disorder, hereditary hemorrhaegic telangiectasia (HHT) (Korzenik etal. 1996). HHT is a genetic disorder involving mutations in endognetic TGFB binding protein. This mechanism based on TGFB function may not only underly the action of genistein in the treatment of HHT, but also in the prevention of cancer and cardiovascular diseases.
Supported by grants from AICR and NCI (CA 61668).
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