Differential regulation of specific genes in MCF-7 and the ICI 182780-resistant cell line MCF-7/182(R)-6

To elucidate the mechanisms involved in anti-oestrogen resistance, two huma n breast cancer cell lines MCF-7 and the ICI 182780-resistant cell line, MC F-7/182(R)-6, have been compared with regard to oestrogen receptor (ER) exp ression, ER function. ER regulation, growth requirements and differentially expressed gene products. MCF-7/182(R)-6 cells express a reduced level of E R protein. The ER protein is functional with respect to binding of oestradi ol and the anti-oestrogens tamoxifen, 4-hydroxy-tamoxifen and ICI 182780, w hereas expression and oestrogen induction of the progesterone receptor is l ost in MCF-7/182(R)-6 cells, The ER protein and the ER mRNA are regulated s imilarly in the two cell lines when subjected to treatment with oestradiol or ICI 182780. Oestradiol down-regulates ER mRNA and ER protein expression. ICI 182780 has no initial effect on ER mRNA expression whereas the ER prot ein revel decreases rapidly in cells treated with ICI 182780, indicating a severely decreased stability of the ER protein when bound to ICI 182780. in vitro growth experiments revealed that the ICI 182780-resistant cell line had evolved to an oestradiol-independent phenotype, able to grow with close to maximal growth rate both in the absence of oestradiol and in the presen ce of ICI 182780. Comparison of gene expression between the two cell lines revealed relatively few differences, indicating that a limited number of ch anges is involved in the development of anti-oestrogen resistance. Identifi cation of the differentially expressed gene products are currently in progr ess.