Published in Cancer Detection and Prevention 1999; 23(5):375-386.

Differential Expression of and Responsiveness to Transforming Growth Factor-β (TGF-β) Isoforms in Hormone-Dependent and Independent Lines of Mouse Mammary Tumors

Marcelo H. Viegas, M.S., Mariana Salatino, Mercedes Goin, Ph.D., Giselle Peters, M.S., Leticia Labriola, M.S., Jefferson Costa da Cunha, M.S., Claudia Lanari, Ph.D., Eduardo H. Charreau, Ph.D., and Patricia V. Elizalde, Ph.D.

Instituto de Biología y Medicina Experimental IBYME, Obligado 2490, Buenos Aires 1428, Argentina

Address all correspondence and reprint requests to: Patricia V. Elizalde. Ph.D., Laboratory of Molecular Mechanisms of Carcinogenesis. Instituto de Biología y Medicina Experimental (IBYME). Obligado 2490, Buenos Aires 1428, Argentina.

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, -132, and -133 (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/mI 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 lobular HI tumors showed that cell surface type II TGF-13 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.

KEY WORDS: mammary adenocarcinomas, progestins, transforming growth factors, TGF-&beta, TGF-&beta, TGF-&beta, .

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