THE ROLE OF TGF-BETA PRODUCTION IN GROWTH-INHIBITION OF BREAST-TUMOR CELLS BY PROGESTINS

We have studied the influence of synthetic progestins on the estrogen- induced proliferation and type-beta transforming-growth-factor (TGF-be ta) production of 3 breast-tumor cell lines. In long-term growth exper iments, progestins inhibited proliferation of T47D cells, while a spec ific T47D variant and MCF7 cells were not affected, despite the presen ce of functional progesterone receptors. The effect of progestins was biphasic, since an initial stimulation of proliferation was followed b y a prolonged inhibition. This response suggests the involvement of a progestin-induced negative growth regulator. We show here that TGF-bet a s do not fulfill this role since (i) the progestin-induced T47D cell s are not sensitive to TGF-beta 1, -beta 2 or -beta 3, (ii) secretion of TGF-beta s is decreased by progestins in all 3 cell lines, and (iii ) TGF-beta neutralizing antibodies do not reverse progestin-induced gr owth inhibition. Furthermore, evidence was obtained that medium condit ioned by T47D cells does not contain any other growth inhibitor to whi ch this cell line responds in a negative autocrine manner, In contrast , MCF7 cells are growth-inhibited by all 3 TGF-beta isoforms, but are not growth-inhibited by progestins, suggesting that there is no correl ation between growth inhibition by progestins and responsiveness to an d production of TGF-beta in vitro, Although TGF-beta is a strong growt h inhibitor of normal mammary tissue, recent evidence suggests that, i n malignant tissue, enhanced TGF-beta secretion correlates with increa sed malignancy. Therefore, a progestin-induced decrease in TGF-beta pr oduction, as observed here, may lead to enhanced proliferation of norm al but not malignant mammary epithelium. (C) 1995 Wiley-Liss, Inc.