Pennanen Pasi T, Sarvilinna Nanna S, Ylikomi Timo J
Department of Cell Biology, Medical School, University of Tampere, Tampere, Finland.
Anticancer Drugs. 2009 Jan;20(1):51-8. doi: 10.1097/CAD.0b013e32831845e1.
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.
我们分别通过在无雌激素的条件下长期培养，或在有抗雌激素药物托瑞米芬存在的条件下，从激素依赖性MCF-7乳腺癌细胞中建立了雌激素非依赖性和抗雌激素耐药细胞系。通过使用cDNA微阵列，我们比较了雌激素非依赖性、抗雌激素耐药和长期雌激素处理的MCF-7细胞之间的基因表达谱。我们还确定了在细胞系的长期培养过程中差异表达基因的表达是如何发展的。在筛选的1176个癌症相关基因中，发现FOSL1、TIMP1、L1CAM、GDF15和MYBL2在这些细胞系之间存在差异表达。FOSL1和TIMP1表达的变化可能归因于抗雌激素耐药性的发展，而诱导性L1CAM表达与细胞雌激素非依赖性生长的发展有关。雌激素调节基因GDF15和L1CAM在托瑞米芬耐药细胞的后期传代中受托瑞米芬调节，这可能表明托瑞米芬在这些细胞中产生了雌激素激动活性。我们的研究结果表明了一种模式，即激素反应性癌细胞在经历雌激素剥夺和/或抗雌激素治疗后存活下来，首先在基因表达上获得必要的变化，以便在新的激素环境中过渡到最大生长。然后，在用抗雌激素进行长期治疗后，抗雌激素耐药细胞最终可能对抗雌激素产生雌激素激动反应，可能获得额外的生长优势。
