Hormonal modulation of sex steroid hormone receptors and oncogenes in human breast cancer cells

Since sex steroids modulate breast tumor growth, and high levels of the HER-2/neu protooncogene protein may contribute to breast cancer metastasis, the effects of estrogen, progestin and hormone antagonists on the levels of estrogen receptor (ER), progesterone receptor (PR) and HER-2/neu mRNA and protein have been studied in human breast cancer cell lines using cDNA and antibody probes. In all studies, protein response closely followed the RNA response. In MCF-7 cells, which contain high levels of ER and an estradiol (E$\sb2$) induced PR, 1 nM E$\sb2$ caused a 60% drop in ER mRNA (6.6 kb), a 10-fold rise in PR mRNA (5 species: 11.4, 5.8, 5.3, 3.5, 2.8 kb), and a 60% drop in HER-2neu mRNA levels (4.8 kb). These effects were dose-dependent (maximal effects $\geq$ 10$\sp{-10}$M), and were blocked by addition of excess antiestrogen. Treatment with the progestin R5020 (10 nM) partly reversed E$\sb2$ effects on ER. R5020 and the antiprogestin RU486 (10 nM) both reduced PR mRNA levels by 50% but did not change HER-2/neu. In T47D cells, which contain low ER and high PR levels, E$\sb2$ induced ER mRNA 2.5-fold in 2d. In contrast, R5020 reduced both ER mRNA and PR mRNA levels to 20% of control in 2d. RU486 caused an initial 50% drop by 6h followed by a rise to control levels by 48h. In T47D, no hormone studied changed HER-2/neu levels. Conclusions: (1) sex steroid hormones regulate their own receptors at the mRNA and protein levels, (2) progestin antagonizes E$\sb2$ effects, (3) these E$\sb2$ effects are mediated via ER (based on dose-dependence and antiestrogen antagonism), and (4) aggressiveness related to E$\sb2$-treatment in MCF-7 cells is not associated with increased levels of HER-2/neu.U of I OnlyETDs are only available to UIUC Users without author permissio