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.