Calcitonin effects on growth and on selective activation of type II isoenzyme of cyclic adenosine 3':5'-monophosphate-dependent protein kinase in T 47D human breast cancer cells.

The influence of calcitonin on cell growth was examined in the human breast cancer cell line, T 47D. These cells possess specific high-affinity receptors for calcitonin as well as a sensitive calcitonin-responsive adenylate cyclase. In the T 47D cells, low doses of salmon calcitonin initially stimulated cell growth and the incorporation of [3H]thymidine into acid-insoluble macromolecules. This initial stimulation was followed by an inhibitory effect of calcitonin upon cell proliferation, which occurred during the log phase of growth, was dose dependent, and resulted in prolongation of doubling time from 36 to 90 hr. DNA and protein content correlated well with cell number. By 7 to 9 days of treatment, cell numbers of calcitonin-treated cells reached a mean of 66.5 +/- 3.7% of control (p less than 0.001, n = 8) (range, 51.3 to 82.9%). This biphasic effect of calcitonin on T 47D cells was reproduced by human calcitonin and prostaglandin E2 in the order of potency with which they influence adenylate cyclase. Epidermal growth factor (10(-9)M) and insulin (10(-9)M) stimulated the growth of T 47D cells, but this effect was abolished when either hormone was combined with salmon calcitonin (3 x 10(-10)M). Calcitonin specifically activated type II isoenzyme of cyclic adenosine 3':5'-monophosphate-dependent protein kinase in the T 47D cells. In view of other published data relating activation of this isoenzyme to growth regression in cancer cells, this response to calcitonin may be causally related to the inhibitory effect of the hormone upon cell replication in T 47D cells. The mechanism of the early stimulatory effect of calcitonin upon mitogenesis is not explained, although the possibility of stimulation of activity of type I isoenzyme of cAMP-dependent protein kinase has not been entirely excluded in the present experiments.