Interestingly, in cell culture, both tamoxifen and all-trans-retinoic acid have been shown [12,13,14,17] to increase the fraction of TGF-β in its biologically active, as opposed to its latent form. The current method for discriminating between active and latent TGF-β in tissue samples requires the use of frozen sections and immunofluorescence techniques, which are not practical for routine clinical use [36]. As simpler assays become available, however, the issue of possible changes in TGF-β activation status should be readdressed. Retinoids can also affect cellular responsiveness to TGF-βs at the level of receptor expression and downstream events [37,38]. To date, expression of TGF-β receptors and downstream signaling components such as the Smads have not been well-characterized in this rat model, but in our preliminary analyses we saw no effect of retinoids on type I and type II TGF-β receptor expression in the mammary gland (data not shown). At this time, however, we certainly cannot rule out the possibility that tamoxifen and retinoids may be having subtle effects on the TGF-β system at levels other than the regulation of TGF-β expression.