Definition of two distinct mechanisms of action of antiestrogens on human breast cancer cell proliferation using hydroxytriphenylethylenes with high affinity for the estrogen receptor

• Published in: Biochemical and biophysical research communications Vol. 140; no. 2; pp. 523 - 529
• Main Authors: Sutherland, Robert L., Watts, Colin K.W., Ruenitz, Peter C.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 30.10.1986; Elsevier
• Subjects: Applied sciences; Binding, Competitive; Breast Neoplasms - drug therapy; Cell Division - drug effects; Cell Line; Clomiphene - analogs & derivatives; Clomiphene - pharmacology; Estradiol - pharmacology; Estrogen Antagonists - metabolism; Estrogen Antagonists - pharmacology; Exact sciences and technology; Humans; Other techniques and industries; Receptors, Estrogen - drug effects; Stilbenes - pharmacology; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/0006-291X(86)90763-1

Treatment of MCF 7 human breast cancer cells with three high affinity hydroxylated antiestrogens (Kd for the estrogen receptor = 0.11 – 0.45 nM) resulted in biphasic inhibition of cell growth. Administration of 0.1–10 nM of each drug caused a concentration-dependent decrease in cell number to a maximum of 30–40% of control but no further change was observed as the drug concentration was increased to 1 μM. Between 1.0 and 10 μM, however, a further concentration-dependent decrease in cell proliferation was observed. Among these compounds relative potencies paralleled their affinities for estrogen receptor in the 0.1–10 nM range but at micromolar concentrations this relationship did not hold. It is concluded that antiestrogens inhibit cell proliferation by two distinct mechanisms one of which involves the estrogen receptor and the other a mechanism yet to be defined. The parallel changes in cell cycle kinetic parameters accompanying growth inhibition in both concentration ranges i.e. accumulation of cells in the G1 phase at the expense of S phase cells, suggests that both mechanisms may converge on common pathways critical to cell cycle progression.