ALTERED EXPRESSION OF ESTROGEN-REGULATED GENES IN A TAMOXIFEN-RESISTANT AND ICI-164,384 AND ICI-182,780 SENSITIVE HUMAN BREAST-CANCER CELL-LINE, MCF-7 TAM(R)-1/

A stable, tamoxifen-resistant subline, MCF-7/TAM(R)-1, of the human br east cancer cell line MCF-7 has been established in tissue culture aft er long-term treatment with 10(-6) M tamosifen. The MCF-7/TAM(R)-1 cel l line grows equally well in the presence and absence of tamoxifen, wh ereas the steroidal antiestrogens ICI 164,384 and ICI 182,780 exert pr ofound inhibitory activity on cell proliferation, although higher conc entrations are required to inhibit these cells compared to the parent cells. The MCF-7/TAM(R)-1 cells grown in tissue culture deviate from p arent characteristics by the complete lack of expression of progestero ne receptors even when grown with estradiol, by an altered tamoxifen r egulation of M(r) 52,000 cathepsin D synthesis and secretion, and by l ack of tamoxifen stimulation of an estradiol down-regulated M(r), 42,0 00 protein with presumed growth inhibitory function. MCF-7/TAM(R)-1 ce lls are estrogen receptor positive. The estrogen receptors have wild t ype characteristics with respect to (a) binding of estradiol, tamoxife n, and ICI 164,384; (b) estrogen and antiestrogen regulation of the es tradiol-regulated proteins pS2, M(r) 61,000 alpha(1)-antitrypsin-like protein, M(r) 66,000 alpha(1)-antichymotrypsin-like protein, and corre sponding mRNAs; and (c) estrogen and antiestrogen regulation of a tran siently transfected estrogen responsive reporter gene. We suggest that the lack of tamoxifen up-regulation of the M(r) 42,000 protein synthe sis in MCF-7/TAM(R)-1 cells may at least partly explain the resistance to tamoxifen treatment. The sensitivity to the growth inhibitory acti vity of ICI 164,384 and ICI 182,780 may be ascribed to the maintenance of the pure antagonistic effect of these steroidal antiestrogens on M CF-7/TAM(R)-1 cells. Our results indicate that treatment with pure ant iestrogens may be effective when patients become refractory to tamoxif en therapy.