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Tumor Promoter Binding to Rat Mammary Cell Cultures: Role of Receptors in the Inhibition of Dome Formation¹

The Salk Institute, San Diego, California 92138

We have studied the receptors for phorbol ester tumor promoters in a set of cultures of mammary cell lines derived from the same dimethylbenz(a)anthracene-induced tumor. These lines differ in cell morphology and in the ability to form domes either spontaneously or under the action of inducers. Tumor promoters inhibit dome formation. We asked whether receptors for tumor promoters could also mediate dome induction. We were unable to detect high-affinity receptors for the strong promoter, tetradecanoyl-12-phorbol-13-acetate (TPA) but could reveal receptors for the weaker promoter, phorbol-12,13-dibutyrate (PDBU). Receptors were easily demonstrable during PDBU binding at 4°; at 37°, there was rapid disappearance of bound ligand, accompanied by its breakdown. Most cell lines have two classes of receptors with different affinities. Receptors for TPA could be demonstrated by competition with PDBU binding. In LA7 cells, prolonged exposure to PDBU caused down-regulation of the PDBU receptors with lower affinity. The half-effective doses of the dome-inhibiting effects are comparable to the K_ds of the higher-affinity PDBU receptors measured by binding. TPA binds preferentially to the same class of receptors. This class of receptors, therefore, appears to be the one mostly involved in the anti-dome effect of either PDBU or TPA. Because dome inducers do not compete with PDBU binding, the PDBU receptors may not be responsible for dome induction.

¹ This investigation was supported by Grant 1-R01CA 21993 of the National Cancer Institute and by grants from the Hammer Foundation, the Educational Foundation of America, the Pardee Foundation, and the Samuel Roberts Nobel Foundation, Inc. This research was conducted in part by the Clayton Foundation for Research, California Division.

² On leave from the Division of Genetics and Experimental Animals of the Netherlands Cancer Institute, Amsterdam, The Netherlands; funded by a grant from the Queen Wilhelmina Foundation to Dr. J. Hilgers.

³ Senior Clayton Foundation Investigator.

Received 12/ 8/81. Accepted 12/ 6/82.