Cellular and molecular mechanism of action of antiestrogens.

The mechanism of action of tamoxifen and of 4-hydroxytamoxifen is reviewed at the cellular and molecular level, through the current view of the authors. Synthetic antiestrogens are mainly acting directly on breast cancer cells by interacting with the estrogen receptor (RE). They prevent estrogen action by competing with estrogens on the cytosol RE. The resulting complex is partially activated, leading to its nuclear localisation and a partial and dissociated stimulation of the expression of estrogen responsive genes. A defective and partial activation of RE induced by antiestrogen is shown in vitro by several alterations of the RE concerning the dissociation rate of ligands and the affinity for double-stranded DNA and for a monoclonal antibody against the RE. The explanation of the inhibition of tumor growth is more controversial, since the proliferation of estrogen responsive cells is not only regulated by estrogens but also by other hormones and factors. We present evidence of a direct effect of antiestrogen mediated by the RE, and discuss the mechanism of resistance to antiestrogen in RE positive breast cancer cells.