MCF7 LCC9 - AN ANTIESTROGEN-RESISTANT MCF-7 VARIANT IN WHICH ACQUIRED-RESISTANCE TO THE STEROIDAL ANTIESTROGEN ICI-182,780 CONFERS AN EARLYCROSS-RESISTANCE TO THE NONSTEROIDAL ANTIESTROGEN TAMOXIFEN/

Acquired resistance to antiestrogens is a major problem in the clinica l management of initially endocrine responsive metastatic breast cance r, We have shown previously that estrogen-independent and -responsive MCF7/LCC1 human breast cancer cells selected for resistance to the tri phenylethylene tamoxifen produce a variant (MCF7/LCC2) that retains se nsitivity to the steroidal antiestrogen ICI 182,780 (N. Brunner et al. , Cancer Res., 53: 3229-3232, 1993), We have now applied stepwise sele ctions in vitro from 10 pM to 1 mu M ICI 182,780 against MCF7/LCC1 and obtained a stable ICI 182,780-resistant variant designated MCF7/LCC9. In contrast to 4-hydroxytamoxifen-selected MCF7/LCC2 cells, MCF7/LCC9 cells exhibit full cross-resistance to tamoxifen, despite never havin g been exposed to this drug. Significantly, tamoxifen cross-resistance arose early in the selection, appearing following selection against o nly 0.1 nM ICI 182,780, Although limited resistance to ICI 182,780 als o was observed, full ICI 182,780 resistance was not detected until the selective pressure increased to 100 nM ICI 182,780, Cross-resistance to tamoxifen persisted. throughout these additional selections, Despit e their antiestrogen cross-resistance, MCF7/LCC9 cells retain a level of estrogen receptor expression comparable to that of their parental M CF7/LCC1 cells. Whereas MCF7/LCC1 cells retain an estrogen-inducible e xpression of progesterone receptors, MCF7/LCC9 cells exhibit an up-reg ulated expression of both progesterone receptor mRNA and protein that is no longer estrogen responsive, Estrogen-independent and -responsive components of the MCF7/LCC9 phenotype are appal eat in vivo, These ce lls form slowly growing tumors in ovariectomized athymic nude mice but respond mitogenically upon estrogenic supplementation. The in vivo gr owth of MCF7/LCC9 tumors is not affected by treatment with ICI 182,780 . Although there is some evidence of tamoxifen stimulation of tumor gr owth, this did not reach statistical significance, If this pattern of cross-resistance occurs in some breast cancer patients, administering triphenylethylene antiestrogens as a first-line therapy with a cross-o ver to steroidal compounds upon recurrence mag be advantageous.