beta-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells

MDA-MB-231 human breast cancer cells express high beta-adrenoceptor levels, predominantly the beta(2) subtype. Receptor stimulation by isoproterenol e voked immediate reductions in DNA synthesis which were blocked completely b y propranolol and were of the same magnitude as effects elicited by high co ncentrations of 8-Br-cAMP. Isoproterenol-induced inhibition of DNA synthesi s was maintained throughout several days of exposure, resulting in a decrem ent in total cell number, and the effects were augmented by cotreatment wit h dexamethason; an even greater effect was seen when cAMP breakdown was inh ibited by theophylline, with or without addition of isoproterenol. Despite the persistent effect of isoproterenol, receptor downregulation was evident with as little as 1 h of treatment, and over 90% of the receptors were los t within 24 h. Receptor downregulation was paralleled by homologous desensi tization of the adenylyl cyclase response to beta-adrenoceptor stimulation. Dexamethasone augmented the effects of isoproterenol on DNA synthesis but did not prevent receptor downregulation or desensitization. These results i ndicate that beta-adrenoceptors are effectively linked, through cAMP, to th e termination of cell replication in MDA-MB-231 human breast cancer cells, and that activation of only a small number of receptors is sufficient for a maximal effect. Novel pharmacologic strategies that focus on cell surface receptors operating through adenylyl cyclase may offer opportunities to com bat cancers that are unresponsive to hormonal agents, or that have develope d multidrug resistance.