Gene expression changes during the development of estrogen-independent and antiestrogen-resistant growth in breast cancer cell culture models

We have established estrogen-independent and antiestrogen-resistant cell lines from hormone-dependent MCF-7 breast cancer cells by long-term culture in the absence of estrogen, or in the presence of antiestrogen toremifene, respectively. By using a cDNA microarray we compared gene expression profiles among estrogen-independent, antiestrogen-resistant and long-term estrogen-treated MCF-7 cells. We also determined how the expression of the differentially expressed genes has developed during the long-term culture of the cell lines. Of the screened 1176 cancer-related genes, FOSL1, TIMP1, L1CAM, GDF15, and MYBL2 were found to be differentially expressed between the cell lines. A change in FOSL1 and TIMP1 expression could be attributed to the development of antiestrogen resistance, whereas induced L1CAM expression was implicated in the development of estrogen-independent growth of the cells. Estrogen regulated genes GDF15 and L1CAM became regulated by toremifene in the later passage number of toremifene-resistant cells, which might be an indication of the developed estrogen-agonistic activity of toremifene in these cells. Our findings suggest a pattern where the hormone-responsive cancer cells, which survive E2 deprivation and/or antiestrogen treatment, first acquire necessary changes in gene expression for transition to maximal growth in the new hormonal environment. Then, after prolonged treatment with antiestrogen, the antiestrogen-resistant cells may eventually generate an E2-agonistic response to antiestrogen, probably acquiring additional growth advantage.