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In estrogen receptor (ER)+ MCF-7 cells, ER represents a ligand-activated transcription factor, and 17β-estradiol (E2) represents its physiological ligand. Maintenance of the human breast carcinoma-derived MCF-7 cells with 0.7% serum selected a proliferative sub-population of E2-responsive cells with transiently non-functional ER due to limited availability of E2. Culture of MCF-7 cells in the presence of either 0.7% serum, &lt;1 nM E2 or 0.7% serum + 20 nM E2 selected isogenic cells with either non-functional ER (ER-NF) or functional ER (ER-F) phenotype. The two phenotypes responded to the growth-promoting effects of E2 and to the growth-inhibitory effects of the selective ER modulator tamoxifen, indicating retention of E2 responsiveness. Comparative dose-response experiments with Chinese nutritional herbs on ER-NF and ER-F cells identified the inhibitory concentration (IC)50 values for these herbs, while the IC50 ratios for the ER-NF:ER-F phenotypes facilitated their rank ordering in terms of efficacy. Out of the 11 efficacious herbs tested, five herbs exhibited ER-F &gt; ER-NF inhibitory activity, four exhibited ER-F = ER-NF inhibitory activity and two exhibited ER-NF &gt; ER-F inhibitory activity. Extracts from representative herbs, Lycium barbarum bark , Epimedium grandiflorum and Cornus officinalis , from each of the three groups inhibited anchorage-independent growth, induced G 1 or G2/M arrest and/or apoptosis, and generated anti-proliferative E 2 metabolites. The differential growth inhibition in ER-NF and ER-F phenotypes, together with the mechanistic efficacy of representative herbs, identified potential leads for their efficacy on ER + and/or ER- breast cancer.

Inhibitory effects of Chinese nutritional herbs in isogenic breast carcinoma cells with modulated estrogen receptor function