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 (> 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.
Perry
R R
RR
Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk 23507, USA.
Kang
Y
Y
Greaves
B R
BR
D000912:Antibodies, Neoplasm / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D005784:Gene Amplification / Q000187:drug effects; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000912:Antibodies, Neoplasm; D018931:Antineoplastic Agents, Hormonal; D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013629:Tamoxifen