Aim - the impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the effects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treatments. Our aim was to study the effects on breast cancer cell proliferation of EGF, TGFbeta and 17beta-oestradiol, three important regulators of breast tumourigenesis, and their respective inhibitors in different combinations. We screened the effects on proliferation of MCF7 and MDA-MB-231 cells of ninety different combinations of EGF, TGFbeta and 17beta-oestradiol, Iressa, SB431542 and Tamoxifen. Meta-data analysis of available clinical data was performed to validate observed proliferation data. In MDA-MB-231 cells, TGFbeta was found inhibitory when cells were simultaneously treated with EGF and 17beta-oestradiol, with the effect potentiated by addition of all inhibitors combined. In the same cells, Iressa when combined with EGF was paradoxically stimulatory. Tamoxifen inhibited MCF7 cells co-treated with EGF or oestrogen, and enhanced the inhibitory effect of TGFbeta in MDA-MB-231 cells. Meta-analysis of clinical gene expression studies confirmed several of these points, showing enhanced TGFbeta and EGF expression in Tamoxifen-treated patients to correlate with decreased tumour size and grade respectively, and combined TGFbeta-EGF expression to decrease the risk of metastasis. Conclusion: our study shows significant differences in proliferation response to drugs and growth factors between MCF7 cells which do not have propensity to form metastases in animal models and MDA-MB-231 cells which may form metastases upon inoculation into animals. Several of these differences are unexpected and confirmed by clinical observations.

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