ErbB‐2 expression in estrogen‐receptor‐positive breast‐tumor cells is regulated by growth‐modulatory reagents

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Abstract
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′‐cycfic‐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.