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Background: The mechanisms by which tamoxifen inhibits breast tumor growth are not completely understood. Partial agonist antiestrogens such as tamoxifen may cause the estrogen receptor (ER) to interact with genes different from those activated by ER bound to estradiol. Doming is a property often associated with, and considered a marker of, differentiation in mammary epithelial cells in culture. This study compared the ability of pure and partial agonist antiestrogens to stimulate doming. Materials and methods: MCF-7 cells grown in medium with 10% calf serum were treated with antiestrogens. Domes were counted in three rows (width of the 4× field) across the flask. Results: Three partial agonist antiestrogens [4-hydroxytamoxifen (OHT), H1285 and RU 39,411] caused dome formation. None of the pure antiestrogens tested (ICI 164,384, ICI 182,780 and RU 58,668) caused doming. Doming was stimulated in a dose-dependent manner starting at 1 nM OHT with maximum stimulation at 10-100 nM. Estradiol did not stimulate doming, but blocked doming at 1%-10% of the OHT concentration. Trichostatin A (TSA) reduced the level of estrogen receptor alpha (ERα) and adding it 24 h before adding OHT prevented dome formation. Conclusions: OHT and the other partial agonist antiestrogens appear to act through the ER to stimulate doming. The ability of tamoxifen to induce a marker of differentiation may play a role in its inhibition of breast tumors. If so, then the fact that other partial agonist antiestrogens share this ability, but that pure antiestrogens lack it, may be an important consideration in developing new antiestrogens for breast cancer therapy. [ABSTRACT FROM AUTHOR]