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ICI 164,384, a Pure Antagonist of Estrogen-stimulated MCF-7 Cell Proliferation and Invasiveness¹

Laboratory of Developmental Biology and Anomalies, NIDR, NIH, Bethesda, Maryland 20892 [E. W. T., T. B. S.]; Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd., NW Washington, DC 20007 [D. K., M. E. L., R. B. D.]; and ICI Pharmaceuticals, Alderly Park, Macclesfield, Cheshire, England [A. E. W.]

Estrogen is known to stimulate the proliferation and basement membrane invasiveness of the MCF-7 human breast cancer cell line. We have compared the new steroidal antiestrogen ICI 164,384, the triphenylethylene 4-hydroxytamoxifen (OHT), and the benzothiophene LY 117018, for their effects on the proliferation and invasiveness of the MCF-7 cell line and its antiestrogen-resistant variant LY-2. While all three antiestrogens blocked the proliferative effects of 17ß-estradiol on MCF-7 cells, OHT and LY 117018, but not ICI 164,384 stimulated their proliferation in the absence of estrogen. The proliferative effects of OHT and LY 117018 were blocked by ICI 164,384. Basement membrane invasiveness of MCF-7 cells was stimulated by 17ß-estradiol and OHT, but not LY 117018 or ICI 164,384. Both ICI 164,384 and LY 117018 were able to block the invasiveness induced by either 17ß-estradiol or OHT. The LY-2 antiestrogen-resistant variant of the MCF-7 cell line showed increased basal proliferation, and responded only slightly to estrogen. ICI 164,384, but not OHT or LY 117018 antagonized the effects of 17ß-estradiol, but did not reduce proliferation below control levels. The LY-2 line was not resistant to the antiestrogenic effects of LY 117018 or ICI 164,384 on invasiveness, and was stimulated by LY 117018 for this parameter. Thus, ICI 164,384 is a pure antiestrogen for MCF-7 cell proliferation and invasiveness, and may offer clinical advantage over nonsteroidal antiestrogens which can stimulate these activities in tumor models in vitro.

¹ This work, Erik W. Thompson, and Thomas B. Shima were supported in part by the Breast Cancer Study Group, National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007.

Received 2/ 3/89. Revised 8/28/89. Accepted 9/21/89.