Transforming growth factor-beta and breast cancer: Lessons learned from genetically altered mouse models

The hypothesis that transforming growth factor (TGF)-βs may act as a tumor suppressors in the mammary gland has considerable intuitive appeal. TGF-βs are expressed at all stages of mammary development except lactation [1], and they have potent growth inhibitory effects on mammary epithelial cells in vitro and in vivo [2,3]. Furthermore, many breast cancer cell lines have absent or decreased TGF-β responsiveness [4], and decreased expression of the type II TGF-β receptor in early premalignant breast lesions is correlated with increased probability of subsequent invasive disease [5]. TGF-βs also have pro-oncogenic activities, however, and advanced human breast tumors overexpress TGF-βs [6]. This suggests that the role of TGF-βs in breast cancer is probably complex. The potential oncogenic and tumor suppressor activities of TGF-βs are summarized in Figure 1.We propose that TGF-βs are 'conditional tumor suppressors', with suppressor activity depending on a variety of factors, including the TGF-β responsiveness of the mammary epithelium, the stage in tumorigenesis, the nature of cooperating oncogenic events, and the level of expression of TGF-β ligand and receptor. It will be critical to define the precise circumstances under which TGF-βs act as tumor suppressors in the breast if we are to exploit the TGF-β system for therapy and/or prevention of breast cancer. Genetically engineered mouse models provide an invaluable experimental tool for this purpose, because TGF-β function can be manipulated in the context of the intact organism, where complex tissue interactions and regulatory cues are maintained. Also, whereas analysis of clinical samples can reveal provocative correlations between altered gene expression and tumorigenesis, animal studies allow causal mechanistic connections to be established.To date, there are five mouse models that have been generated specifically to elucidate TGF-β function in the mammary gland (Table 1), and two more that give some insight into