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DOI: 10.1055/s-0035-1547629
4-Hydroxy-N-Demethyltamoxifen (4OHNDTAM, Endoxifen) down-regulates Cytokeratin 6 (CK6) IN MCF-7 breast cancer cells
Introduction:
Tamoxifen is an anti-estrogen drug used in the treatment of Estrogen Receptor (ER) positive breast cancer. 4-Hydroxy-N-demethyltamoxifen (4OHNDtam, endoxifen) is considered the main active metabolite of tamoxifen. In this study we investigated the gene regulatory effects of the three metabolites of tamoxifen in MCF-7 breast cancer cells.
Material and Methods:
We examined effects of 4-Hydroxytamoxifen (4OHtam), 4OHNDtam, and Ndesmethyltamoxifen (NDtam) on global gene expression in 17β-estradiol (E2) treated MCF-7 cells. Transcriptomic responses were assessed by correspondence analysis, differential expression and gene ontology analysis, and expression of individual genes was validated by quantitative real time PCR (Q-rt-PCR). E2 deprivation was performed to further characterize specific effects on gene expression.
Results:
4OHNDtam and 4OHtam caused major changes in gene expression compared to treatment with E2 alone, with a stronger effect of 4OHNDtam. NDtam had nearly no effect on the global gene expression profile compared to the E2 treated MCF-7 cells. Treatment of MCF-7 cells with 4OHNDtam led to a strong down-regulation of all the CytoKeratin 6 isoforms (KRT6A, KRT6B and KRT6C). The CytoKeratin 6 mRNAs were also down-regulated in MCF-7 cells after E2 deprivation.
Conclusion:
Using concentrations that mimic the clinical situation we report global gene expression changes that were most pronounced with 4OHNDtam and minimal with NDtam. Genes encoding CytoKeratin 6 were highly down-regulated by 4OHNDtam after E2 deprivation indicating an estrogen receptor-dependent regulation.