Differential expression of and responsiveness to transforming growth factor-beta (TGF-beta) isoforms in hormone-dependent and independent lines of mouse mammary tumors

Transforming growth factor-beta 2 (TGF-beta 2) and -beta 3 mRNA expressions were studied in ductal hormone-dependent (HD) and -independent (HI) in viv o lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor mode l in Balb/c mice. MPA treatment of HD tumors induced a significant decrease in TGF-beta 2 and -beta 3 mRNA levels. Progression to an HI phenotype of d uctal tumors was associated with reduced TGF-beta 2 and -beta 3 expressions , as compared with their HD counterparts. Exogenously added TGF-beta 1, -be ta 2, and -beta 3 (1 ng/ml) inhibited the proliferation of primary cultures of epithelial cells from ductal HD and HI tumors. In addition, TGF-beta ex pression and effects were studied in the other type of MPA-induced mammary tumors, which are of lobular origin and lack steroid hormone receptors and evidence an HI behavior. These lobular HI lines showed TGF-beta 2 levels si milar to those found in HD lines growing in MPA-treated mice. In contrast, TGF-beta 3 mRNA levels were 12- to 20-fold higher than in HD tumors. Primar y cultures of lobular HI epithelial cells required either TGF-beta concentr ations of 10 ng/ml to show an inhibitory response, or were completely resis tant to TGF-beta inhibition. Studies of the molecular mechanisms involved i n reduction or loss of TGF-beta responsiveness in lobular HI tumors showed that cell surface type II TGF-beta receptor levels were lower in these tumo rs than those present in HD tumors. Our results support the hypothesis that TGF-beta could play a role as an autocrine growth inhibitor in HD and HI d uctal tumors. Autonomous growth of lobular HI tumors could be favored by un detectable or low TGF-beta 1 and -beta 2 expressions and by reduced or lost sensitivity of epithelial cells to TGF-beta's antiproliferative effects. H owever, the extremely high levels of TGF-beta 3 expression in lobular HI tu mors, in spite of reduced sensitivity to TGF-beta 3 inhibitory growth effec t in tumor epithelial cells, suggest a net positive role for TGF-beta 3 in these tumors.