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CELLULAR AND MOLECULAR

Endoxifen, a Secondary Metabolite of Tamoxifen, and 4-OH-Tamoxifen Induce Similar Changes in Global Gene Expression Patterns in MCF-7 Breast Cancer Cells

Division of Clinical Pharmacology (Y.C.L., Z.D., D.A.F., T.C.S.) and Division of Biostatistics (L.L., Q.Z.), Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Research Institute of Medical Sciences, Chonnam National University and Clinical Trial Center, Chonnam National University Hospital, Kwangju, Korea (Y.C.L.); and Division of Hematology Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan (J.M.R.)

We recently demonstrated that endoxifen (4-hydroxy-N-desmethyl-tamoxifen), a pharmacogenetically regulated metabolite of tamoxifen, is equipotent to 4-hydroxy-tamoxifen (4-OH-Tam) with respect to estrogen receptor binding and inhibition of 17-estradiol (E₂)-induced cell proliferation. Endoxifen was also found to be more abundant in human plasma than 4-OH-Tam, and its formation has been shown to be primarily catalyzed by cytochrome P450 2D6 (CYP2D6). Here, we report studies evaluating the effects of endoxifen, 4-OH-Tam, and E₂ on gene expression in MCF-7 cells using Affymetrix U133A GeneChip Arrays (Santa Clara, CA). We detected 4062 genes that were E₂-regulated (1924 induced; 2138 suppressed), and the ratio of E₂-induced versus E₂-suppressed genes was consistent regardless of the cutoff value. In the presence of E₂, 2444 and 2390 genes were affected by 4-OH-Tam and endoxifen, respectively, when no minimal -fold change cutoff was implemented. The majority of genes regulated by the tamoxifen metabolites were also E₂-responsive (74.4 and 73.3%, respectively). Endoxifen and 4-OH-Tam had overlapping effects on 1365 E₂-sensitive genes, whose -fold effects between these metabolites were highly correlated (R² = 0.99). A significant correlation was also found between the -fold effects of 249 E₂-insensitive genes coregulated by both metabolites (R² = 0.99). Hierarchical clustering analysis demonstrated similar gene regulation patterns between these metabolites, which were distinct from E₂ or vehicle treatment patterns. Using real time-polymerase chain reaction, we validated the gene expression patterns of five genes that were differentially regulated by endoxifen and 4-OH-Tam. We conclude that endoxifen and 4-OH-Tam have similar effects on global gene expression patterns in MCF-7 cells and that the majority of the affected genes are estrogen-regulated genes.

Address correspondence to: Dr. Todd C. Skaar, Division of Clinical Pharmacology, Indiana University School of Medicine, 1001 West 10th Street, WD Myers Bldg., W7123, Indianapolis, IN 46202. E-mail: tskaar{at}iupui.edu

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