Lack of effect of chemopreventive agents on TGF-β expression may have positive implications
There is considerable evidence to suggest that, at late stages in tumorigenesis, TGF-βs can actually promote the tumorigenic process, particularly if the epithelial cells have lost responsiveness to the growth regulatory effects of TGF-β by this time [9,39,40,41]. Thus, advanced human tumors show increased levels of TGF-β expression [42,43,44], and TGF-βs are known to suppress the immunosurveillance system, to enhance angiogenesis, invasion and metastasis, and to increase drug resistance [45,46,47,48].
In the colon, loss of the type II TGF-β receptor occurs at the late adenoma to carcinoma transition [49], suggesting that early premalignant lesions retain TGF-β responsiveness and would be amenable to interventions that enhance TGF-β activity. However, while the present work was in progress, a study was reported [25] showing that loss of the type II TGF-β receptor can already be seen in a significant fraction of hyperplasias without atypia in the human breast. Furthermore, loss of the receptor correlated with increased risk of subsequently developing invasive breast cancer. Thus, unlike in the colon, loss of TGF-β response may be a very early event in the development of human breast cancer.
Since locally elevated TGF-β levels may select for TGF-β-resistant cells, and because TGF-βs can have oncogenic effects on the stroma, it may actually be important for the safety profile of chemopreventive agents to demonstrate that they do not increase TGF-β levels in the at-risk breast. For example, tamoxifen resistance in a xenograft model of advanced human breast cancer, was recently shown [50] to be associated with an increase in TGF-βs and concomitant immunosuppressive effects on natural killer cells. In this regard, our demonstration that the expression of TGF-βs in the preclinical rat model is unaffected by tamoxifen, 9cRA, and 4-HPR may actually have positive implications, because these agents are already in clinical use.