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Resonses to Retinoic Acid of Tamoxifen-sensitive and -resistant Sublines of Human Breast Cancer Cell Line MCF-7¹

Department of Biology, Indiana University of Pennsylvania, Indiana, Pennsylvania 15705 [W. B. B.], and Department of Medicine, University of Maryland Cancer Center, Baltimore, Maryland 21201 [J. A. F.]

Growth of the human breast cancer cell line MCF-7 is known to be inhibited both by antiestrogens such as 4-hydroxytamoxifen (OHTAM) and by retinoic acid (RA). Uncloned MCF-7 cells (UNC) and two cloned sublines, one sensitive to antiestrogens (E-3) and the other resistant to them (RR), were used in this study. Growth of UNC and E-3 was inhibited by either OHTAM (10^-7 M) or RA (10^-6 M), and this inhibition could not be overcome by the simultaneous addition of estradiol. Subline RR, which was originally selected for resistance to tamoxifen, was resistant to both OHTAM and RA as measured by either growth in culture or colony forming ability. RR was resistant to RA at all concentrations tested between 10^-9 M and 10^-6 M. The inhibition of uncloned MCF-7 cells by RA was dose dependent between 10^-9 M and 10^-6 M. Subline E-3, however, exhibited a mixed response to RA. At 10^-9 M and 10^-8 M, growth was stimulated, but at 10^-7 M and 10^-6 M it was inhibited. The level of estrogen receptor was measured in the same experiment by using a whole cell assay. In the uncloned MCF-7 cultures and in both the RR and E-3 sublines the level of estrogen receptor was increased between 50 and 200% by RA.

The production of plasminogen activator by MCF-7 cells is stimulated by estrogen. RA had a dual effect on plasminogen activator production. In the absence of estrogen, RA inhibited production below the unstimulated level, but in cells stimulated by estrogen, RA increased plasminogen activator production. The results reported here support possible interactions between the mechanisms by which cells respond to estrogen, antiestrogens, and retinoids.

¹ Supported by USPHS Grants CA-21606 and CA-43868; by Senate Fellowship Grants from Indiana University of Pennsylvania; and Grants from the Faculty Professional Development Council of the State System of Higher Education, Commonwealth of Pennsylvania.

² To whom requests for reprints should be addressed, at Department of Biology, Indiana University of Pennsylvania, Indiana, PA 15705.

Received 1/17/90. Accepted 9/ 9/92.

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