Abstract:

Transforming growth factor-β2 (TGF-β2) and -β3 mRNA expressions were studied in ductal hormone-dependent (HD) and -independent (HI) in vivo lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor model in Balb/c mice. MPA treatment of HD tumors induced a significant decrease in TGF-β2 and -β3 mRNA levels. Progression to an HI phenotype of ductal tumors was associated with reduced TGF-β2 and -β3 expressions, as compared with their HD counterparts. Exogenously added TGF-β1, -β2, and -β3 (1 ng/ml) inhibited the proliferation of primary cultures of epithelial cells from ductal HD and HI tumors. In addition, TGF-β expression 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-β2 levels similar to those found in HD lines growing in MPA-treated mice. In contrast, TGF-β3 mRNA levels were 12- to 20-fold higher than in HD tumors. Primary cultures of lobular HI epithelial cells required either TGF-β concentrations of 10 ng/ml to show an inhibitory response, or were completely resistant to TGF-β inhibition. Studies of the molecular mechanisms involved in reduction or loss of TGF-β responsiveness in q HI tumors showed that cell surface type II TGF-β receptor levels were lower in these tumors than those present in HD tumors. Our results support the hypothesis that TGF-β could play a role as an autocrine growth inhibitor in HD and HI ductal tumors. Autonomous growth of lobular HI tumors could be favored by undetectable or low TGF-β1 and -β2 expressions and by reduced or lost sensitivity of epithelial cells to TGF-β's antiproliferative effects. However, the extremely high levels of TGF-β3 expression in lobular HI tumors, in spite of reduced sensitivity to TGF-β3 inhibitory growth effect in tumor epithelial cells, suggest a net positive role for TGF-β3 in these tumors.