RELATIONSHIP BETWEEN TAMOXIFEN-INDUCED TRANSFORMING GROWTH-FACTOR BETA(1) EXPRESSION, CYTOSTASIS AND APOPTOSIS IN HUMAN BREAST-CANCER CELLS

Previously we have shown that tamoxifen (TAM) induces morphological and biochemical changes typical of apoptosis in oestrogen receptor (ER)-positive MCF-7 or ER-negative MDA-231 human breast cancer cells. In this study the effects of TAM on expression of transforming growth factor beta(1) (TGF-beta(1)) were correlated with the effects on cell cycle kinetics and apoptosis. TAM had similar biphasic effects on both cell lines. Short-term (<6 h) TAM incubation resulted in a slight decrease in TGF-beta(1) protein despite an increase in TGF-beta(1) mRNA and was associated with an increase in cells in S-phase. No apoptotic effects were noted. Longer (greater than or equal to 12 h) TAM incubation induced TGF-beta(1) protein (about 3-fold) and mRNA expression (about 2-fold) in both cell lines, and was associated with G(1)/G(0) blockade and induction of apoptosis. The accumulation of TAM-induced TGF-beta(1) mRNA was increased by cycloheximide, but was not affected by 17 beta-oestradiol. Long-term incubation with TAM had no significant effect on TGF-beta(1) gene copy number. TAM-induced internucleosomal DNA cleavage was inhibited in both cell lines by the addition of an anti-TGF-beta(1) antibody. TAM has dose- and time-dependent effects on TCF-beta(1) expression associated with changes in cell cycle kinetics. These effects are independent of ER status and may be the result of a direct regulatory effect of TAM on TGF-beta(1) transcription. It also appears that induction of TGF-beta(1) plays an important role in TAM-induced apoptosis in breast cancer cells.