Calcitonin-suppressed expression of parathyroid hormone-related protein inbreast cancer cells

Parathyroid hormone-related protein (PTHrP) is a key factor behind humoral hypercalcemia of malignancy (HHM). It is produced in most breast tumors and may be an important local mediator of skeletal metastases due to breast; c ancer. PTHrP may mediate local bone destruction in the absence of increased circulating PTHrP. Calcitonin (CT) is used for treatment of HRM, but there are data showing that CT can increase PTHrP expression and secretion in vi tro. We have therefore studied the effect of GT on PTHrP gene expression an d secretion in MCF-7 breast cancer cells. PTHrP mRNA decreased significantl y after 4, 8, and 16 h incubation with 10 nM salmon calcitonin (sCT) when c ompared with the respective controls. PTHrP mRNA also decreased significant ly and dose-dependently after incubation with sCT at 0.1 to 10 nM for 16 h. The PTHrP levels in the conditioned medium also decreased in a similar dos e-dependent manner. The adenylate cyclase agonist forskolin lowered the PTH rP mRNA dose-dependently. In cells exposed to varying concentrations of sCT for 15 min, the cAMP levels increased dose-dependently. In conclusion, sCT can suppress PTRrP gene expression in MCF-7 breast cancer cells. The suppr essive effect is probably exerted mainly via the cAMP-protein kinase A path ways. (C) 1999 Academic Press.