erbB-2 expression in estrogen-receptor-positive breast-tumor cells is regulated by growth-modulatory reagents

It has previously been shown that, in the estrogen-receptor-positive breast-tumor cell lines T47D and ZR75.1, the erbB-2 protein and mRNA content are controlled negatively and positively by, respectively, estrogens and anti-estrogens. Since estrogens have a positive effect on cell proliferation, while anti-estrogens inhibit cell growth, the results suggested that there may be an inverse correlation between growth and erbB-2 expression. We have now examined this matter further. The effect of various growth-modulatory agents including estrogen (E2), progesterone (Pg), retinoic acid (RA), epidermal growth factor (EGF), insulin (Ins), prolactin (Prl), 12-O-tetradecanolyl-phorbol-13-acetate (TPA) and dibutyryl-3':5'-cyclic-AMP (cAMP) on c-erbB-2 promoter activity, RNA and protein expression have been examined. The growth stimulators E2 and EGF both reduced the level of erbB-2 protein. However, while E2 clearly repressed erbB-2 transcription, in the case of EGF, neither mRNA nor transcription were decreased. Of the agents which inhibit the growth of T47D and ZR75.1 cells--Pg, Prl, cAMP, RA and TPA--only Pg and cAMP caused an increase in the erbB-2 protein level. Pg and cAMP positively influenced c-erbB-2 promoter activity and RNA amount. TPA and RA also increased promoter activity but neither erbB-2 mRNA nor protein level was enhanced. The erbB-2 protein expression in cultures of T47D and ZR75.1 cells at different densities was also analyzed. Both the level of erbB-2 protein and c-erbB-2 promoter activity rose markedly in confluent cultures, suggesting a transcriptional mechanism of control. In conclusion, the data suggest that the effects of various agents on erbB-2 expression are complex and cannot be explained simply as reflecting the growth state of the cells.