TGF-alpha exerts biphasic effects on estrogen- and phytoestrogen-mediated gene expression in breast cancer cells

Transforming growth factor-alpha (TGF-alpha) contributes to the progression of mammary carcinogenesis in part through synergistic augmentation of estr adiol (E-2) action. To investigate this further, we sought to determine (1) whether the duration of TGF-alpha treatment might influence the nature of the TGF-alpha/E-2 interaction, and (2) whether TGF-alpha would behave in a similar manner when combined with phytoestrogens. To this end, we transfect ed T47-D breast cancer cells with an estrogen-responsive reporter and then treated the cells (for 4-48 h) with varying concentrations of TGF-alpha,E-2 , the antiestrogen 4-hydroxy-tamoxifen (HOT), and/or one of three phytoestr ogens. Our findings revealed that TGF-alpha has short-term synergistic and long-term inhibitory effects on E-2- and phytoestrogen-regulated gene expre ssion. Furthermore, this secondary inhibition of E-2 action by TGF-alpha wa s similar in magnitude to that imposed by HOT. These findings demonstrate a novel role for TGF-alpha and invite reevaluation of current models regardi ng TGF-alpha s interactions with E-2 in breast cancer cells. Our results al so raise the possibility that phytoestrogens, which interact with TGF-alpha in a manner conceptually identical to that of E-2, may subserve a regulato ry function in breast cancer cells.