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Potential Role for Retinoic Acid Receptor- in the Inhibition of Breast Cancer Cells by Selective Retinoids and Interferous¹

Sidney Kimmel Cancer Center, La Jolla, California 92037 [A. N. F., H. B., M. F.], and SRI International, Menlo Park, California 94025 [M. D.]

Retinoids are known to inhibit the growth of a wide variety of cancer cells, including breast cancer cells. Advances made in recent years in the understanding of the molecular mechanisms of retinoid action have allowed the design of retinoids with selective activities. Such selective retinoids are of particular interest, because they may reduce the number of undesirable side effects observed with natural compounds. Here, we have compared the growth-inhibitory activities of natural retinoids with various selective retinoids, including anti-activator protein (AP)-1 selective compounds on estrogen receptor-positive and -negative breast cancer cell lines. In addition, we have investigated cooperativity between selective retinoids and IFNs and have begun to analyze the pathways that these two different growth inhibitors use for antagonizing breast cancer cell proliferation. We observe that several selective retinoids can inhibit breast cancer cells as efficiently as the natural compounds. Anti-AP-1-selective retinoids are as effective as retinoic acid receptor (RAR)-ß/-selective compounds. This lets us conclude that retinoid-induced inhibition of breast cancer cell growth does not require retinoid receptor transactivation. Several synthetic retinoids including anti-AP-1-selective compounds show synergism with IFNs. However, true synergism between the two different types of growth regulators was seen only when both classes of molecules were used at low concentrations. RAR-ß/ and anti-AP-1 selective retinoids, but not RAR--selective compounds, induced increased RAR- mRNA levels. Interestingly, IFNs at elevated concentrations (100 units/ml and higher) also induced increased RAR- expression. Thus, when used at high concentrations, IFNs may activate growth-inhibitory pathways overlapping with those activated by retinoids. Because increased RAR- expression is induced by the two different classes of breast cancer cell inhibitors, it is likely to have an important role in controlling the growth of these cancer cells.

¹ This work was supported by NIH Grants CA55681 (M. P.) and CA51993 (M. D. and M. P.). Some of this work was carried out in our previous laboratories at the La Jolla Cancer Research Foundation.

² To whom requests for reprints should be addressed, at Sidney Kimmel Cancer Center, 11099 North Torrey Pines Road, Suite 250, La Jolla, CA 92037. Phone: (619) 623-9632; Fax: (619) 623-9628.

Received 8/11/95. Accepted 1/30/96.

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