In an attempt to approach the mechanism by which estrogen and antiestrogen regulate the growth of estrogen receptor-positive breast cancer, we have studied the effects of the antiestrogens tamoxifen (TAM) and 4-hydroxytamoxifen (OH-TAM) on the induction of two estrogen-specific proteins in a variant of MCF7 cells termed R27, cloned for its ability to grow in the presence of TAM.

We found that, in the R27 variant, antiestrogens as well as estradiol were able to increase specifically the production of a Mr 52,000 protein which was released into the culture medium. This protein was shown to be identical to the Mr 52,000 glycoprotein induced by estrogen and released by MCF7 cells3 on the basis of its specific inducibility by physiological concentrations of 17β-estradiol and of its resolution in two-dimensional gel analysis. Dose-response analysis showed that, in the R27 variant, TAM and OH-TAM acquired the ability to induce the Mr 52,000 protein at concentrations compatible with their relative affinities for the estrogen receptor, while these antiestrogens were inefficient in the wild MCF7 cells. Whereas the relative increase of the Mr 52,000 protein was similar with TAM, OH-TAM, and 17β-estradiol, the general production of Mr 52,000 and of total labeled proteins was less with the antiestrogens than with 17β-estradiol. Moreover, OH-TAM displayed a biphasic dose-response curve with inhibitory effects at concentrations above 10 nm, suggesting an additional mechanism. Neither TAM nor OH-TAM had any antiestrogenic effect when added in the presence of 17β-estradiol.

In the R27 variant, both estradiol and antiestrogens induced the progesterone receptor sites; however, the extent of the stimulation was lower with antiestrogens than with estradiol.

This study shows that, in addition to the classical antiestrogen-resistant breast cancer cells, in which the estrogen receptor is absent or inactive, there is another class of antiestrogen-resistant cells in which the drug becomes a full estrogen agonist as evidenced by the induction of the Mr 52,000 estrogen-specific protein, which is not induced in the wild-type cells.

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This work was supported by Institut National de la Santé et de la Recherche Médicale (PRC, “Aspects Fondamentaux de la Cancérogénèse, No. 118016) and Centre National de la Recherche Scientifique (ATP No. 033826).

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