BREAST-CANCER CELL RESPONSE TO CALCITONIN - MODULATION BY GROWTH-REGULATING AGENTS

Calcitonin may induce cyclic AMP production by breast cancer cells and inhibit their growth. The molecular complex leading to cyclic AMP pro duction in response to calcitonin is made of the calcitonin receptor c oupled to the adenylate cyclase by at least one guanine nucleotide-bin ding protein (G-protein, of the G(5) type). Our aim was to determine w hether and how the responses of cells to calcitonin were modulated by growth-regulating agents not directly acting through the cyclic AMP pa thway. We found that the cyclic AMP response to calcitonin was reduced after preincubation of cells with the mitogens 17 beta-estradiol and epidermal growth factor(EGF), while it was enhanced after preincubatio n with the growth inhibitors tamoxifen and 1,25(OH)(2)D-3, as well as with an antisense oligonucleotide to the proto-oncogene c-myc. Scatcha rd-plots revealed no significant change in the calcitonin receptor num ber or affinity. On the other hand, the cyclic AMP production of cells in response to activators unrelated to calcitonin, such as forskolin, a direct adenylate cyclase effector, and isoproterenol, a beta-adrene rgic receptor agonist, was modulated only weakly or not at all by the growth-regulating agents. This suggested that the effects observed wer e essentially calcitonin-specific and associated with events located b etween the calcitonin receptor and the adenylate cyclase. Since. a G(0 )- or G(1)-protein has been previously implicated in the calcitonin si gnal transduction, we tested the action of pertussis toxin, a specific inhibitor of these G-proteins. Pertussis toxin produced a general inc rease in the cyclic AMP response of cell to calcitonin: moreover, the toxin almost abolished the effect of mitogens and antimitogens an that parameter. We conclude that in breast cancer cells, the calcitonin re ceptor and the adenylate cyclase are coupled by at least one G(0)/G(1) -protein sensitive to growth-regulating agents; this results in a modu lation of the cyclic AMP response to calcitonin by these agents. On th e other hand, the growth-inhibitory effect of calcitonin on breast can cer cells was reduced by 17 beta-estradiol and enhanced by tamoxifen. We suggest that this could be a consequence of changes in cyclic AMP l evels and deserves further investigation. (C) 1998 Elsevier Science B. V.