1,25-DIHYDROXYVITAMIN D-3 ENHANCES THE EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND ITS LATENT FORM BINDING-PROTEIN IN CULTURED BREAST-CARCINOMA CELLS

Transforming growth factor beta s (TGF-beta s) are a family of polypep tide growth factors that regulate cellular growth, phenotype, and diff erentiation. TGF-beta s are synthesized as latent high molecular weigh t complexes that include the NH2-terminal remnant of the TGF-beta prec ursor (latency-associated protein) and, frequently, latent TGF-beta bi nding protein. After activation, TGF-beta s act as local mediators of hormonal responses in target tissues. TGF-beta functions as a negative growth regulator for both breast cancer cells and normal mammary epit helial cells. Vitamin D-3 is growth inhibitory for the estrogen recept or-negative breast cancer cell line BT-20 and regulates TGF-beta expre ssion in cultured keratinocytes. We studied here the effects of vitami n D-3 and its analogues on TGF-beta expression and activity in BT-20 c ells. It was found that vitamin D-3 enhanced both TGF-beta 1 mRNA and secretion of the protein in a time and dose-dependent manner. Analyses of the vitamin D-3 responses in the presence of cycloheximide or acti nomycin D indicated that the TGF-beta 1 mRNA induction was dependent o n both protein and RNA synthesis. The amounts of latent TGF-beta bindi ng protein were also increased in the conditioned medium but not in th e pericellular matrix of vitamin D-3-treated cultures. The amounts of active TGF-beta were enhanced in vitamin D-3-treated cultures as well, suggesting autocrine or paracrine functions for the secreted growth f actor. Some analogues of vitamin D-3 (EB 1089, MC 903, and KH 1060) th at are known to be potent inhibitors of breast cancer cell growth both in vitro and in vivo had similar or more pronounced inducing effects on TGF-beta 1 mRNA levels. The present results indicate that vitamin D -3 and its analogues are potent inducers of both active and latent for ms of TGF-beta 1 in BT-20 breast carcinoma cells and provide evidence for coordinated regulation of latent TGF-beta binding protein and TGF- beta 1.