The role of TGF‐β production in growth inhibition of breast‐tumor cells by progestins

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Abstract
We have studied the influence of synthetic progestins on the estrogen‐induced proliferation and type‐β transforming‐growth‐factor (TGF‐β) production of 3 breast‐tumor cell lines. In long‐term growth experiments, progestins inhibited proliferation of T47D cells, while a specific T47D variant and MCF7 cells were not affected, despite the presence of functional progesterone receptors. The effect of progestins was biphasic, since an initial stimulation of proliferation was followed by a prolonged inhibition. This response suggests the involvement of a progestin‐induced negative growth regulator. We show here that TGF‐βs do not fulfill this role since (i) the progestin‐induced T47D cells are not sensitive to TGF‐βI, ‐β2 or ‐β3, (ii) secretion of TGF‐βs is decreased by progestins in all 3 cell lines, and (iii) TGF‐β neutralizing antibodies do not reverse progestin‐induced growth inhibition. Furthermore, evidence was obtained that medium conditioned by T47D cells does not contain any other growth inhibitor to which this cell line responds in a negative autocrine manner. In contrast, MCF7 cells are growth‐inhibited by all 3 TGF‐β isoforms, but are not growth‐inhibited by progestins, suggesting that there is no correlation between growth inhibition by progestins and responsiveness to and production of TGF‐β in vitro. Although TGF‐β is a strong growth inhibitor of normal mammary tissue, recent evidence suggests that, in malignant tissue, enhanced TGF‐β secretion correlates with increased malignancy. Therefore, a progestin‐induced decrease in TGF‐β production, as observed here, may lead to enhanced proliferation of normal but not malignant mammary epithelium. © 1995 Wiley‐Liss, Inc.