The established human
breast cancer cell line MCF-7 resorbs bone directly in vitro independently of viable endogenous bone cells, and this resorption of bone is closely correlated with the release of hydrolytic
enzymes by the cultured tumor cells. In this study we have examined the effects of a number of drugs which increase the intracellular cyclic
adenosine 3':5'-monophosphate (
cyclic AMP) content on the release of hydrolytic
enzymes by the
tumor cells and their capacity to resorb bone. When MCF-7 cultures were treated with
cholera toxin (0.05 to 5 micrograms/ml), a potent
adenylate cyclase inducer,
mineral-releasing, lysosomal
enzyme, and collagenolytic activities increased more than 2-fold in the cell culture medium.
Prostaglandin E1 (0.1 microM), 8-bromocyclic
AMP (10 mM), and isobutylmethylxanthine (30 microM) caused similar effects. These data suggest that
adenylate cyclase activation and increases in
cyclic AMP content in the
tumor cells caused the release of lysosomal
enzymes and collagenolytic activity and caused the resorption of bone. We have previously found that
colchicine, a
drug which inhibits microtubule assembly, also increased hydrolytic
enzyme release and release of
bone-resorbing activity. Direct measurements of
cyclic AMP were made in MCF-7 cells 3 hr
after treatment with
colchicine (10 microM) as well as MCF-7 cells treated with
prostaglandin E1,
cholera toxin, and isobutylmethylxanthine. MCF-7 cells showed a 2-fold increase in
cyclic AMP content
after treatment with all of these agents, although there was no similar increase in mouse 3T3 cells which do not produce
bone-resorbing activity under these conditions. These data suggest that increases in
cyclic AMP concentrations in human
breast cancer cells lead to release of hydrolytic
enzymes and resorption of bone.