Perry R R, Kang Y, Greaves B R
Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk 23507, USA.
Br J Cancer. 1995 Dec;72(6):1441-6. doi: 10.1038/bjc.1995.527.
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 (> or = 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 G1/G0 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 TGF-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.
此前我们已经表明，他莫昔芬（TAM）可诱导雌激素受体（ER）阳性的MCF-7或ER阴性的MDA-231人乳腺癌细胞发生典型的凋亡形态学和生化变化。在本研究中，TAM对转化生长因子β1（TGF-β1）表达的影响与对细胞周期动力学和凋亡的影响相关。TAM对两种细胞系都有类似的双相效应。短期（<6小时）TAM孵育导致TGF-β1蛋白略有下降，尽管TGF-β1 mRNA增加，且与S期细胞增加有关。未观察到凋亡效应。较长时间（≥12小时）TAM孵育诱导两种细胞系中TGF-β1蛋白（约3倍）和mRNA表达（约2倍），并与G1/G0期阻滞和凋亡诱导有关。放线菌酮增加了TAM诱导的TGF-β1 mRNA的积累，但不受17β-雌二醇影响。长期TAM孵育对TGF-β1基因拷贝数无显著影响。添加抗TGF-β1抗体可抑制两种细胞系中TAM诱导的核小体间DNA裂解。TAM对TGF-β1表达具有剂量和时间依赖性效应，与细胞周期动力学变化相关。这些效应与ER状态无关，可能是TAM对TGF-β1转录直接调控作用的结果。似乎TGF-β1的诱导在TAM诱导的乳腺癌细胞凋亡中起重要作用。
