Partial antagonism between steroidal and nonsteroidal antiestrogens in human breast cancer cell lines.

Nonsteroidal antiestrogens, such as tamoxifen, are well established in the treatment of breast cancer. The development of new steroidal compounds without partial agonist activity allows deeper insights into the mechanism of antiestrogen action, but thus far, the combined use of steroidal and nonsteroidal antiestrogens has not been studied extensively. We compared the nonsteroidal 4-trans-hydroxytamoxifen (OHT) with the two steroidal antiestrogens, ICI 182780 and RU 58668, in the estrogen receptor-positive human breast cancer cell lines MCF-7 and T47D. The effect of each compound alone or of OHT in combination with one of the steroidal antiestrogens was studied in regard to cell proliferation, expression of estrogen receptors (ERs) and progesterone receptors, and secretion of transforming growth factor beta2 (TGF-beta2). All antiestrogens examined led to enhanced secretion of TGF-beta2, which is correlated with their individual growth-inhibitory potential. OHT partially counteracts the larger growth inhibition of human breast cancer cells exerted by the steroidal antiestrogens ICI 182780 and RU 58668. Also, OHT antagonizes the higher induction of TGF-beta2 seen after treatment of MCF-7 cells with steroidal antiestrogens. The loss of ER and down-regulation of progesterone receptor under treatment with the steroidal antiestrogens is prevented by OHT, whereas the steroidal antiestrogens prevent the ability of hydroxytamoxifen to increase the ER content. These results indicate that TGF-beta2 is a marker of action for both types of compounds, but steroidal and nonsteroidal antiestrogens partially antagonize each other in blocking ER-mediated cellular events. It would appear that no additive or synergistic effect of the two types of antiestrogens can be expected in the treatment of breast cancer.