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https://hdl.handle.net/2440/53892
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Type: | Journal article |
Title: | A polymorphism in the TC21 promoter associates with an unfavorable tamoxifen treatment outcome in breast cancer |
Author: | Rokavec, M. Schroth, W. Amaral, S. Fritz, P. Antoniadou, L. Glavac, D. Simon, W. Schwab, M. Eichelbaum, M. Brauch, H. |
Citation: | Cancer Research, 2008; 68(23):9799-9808 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2008 |
ISSN: | 0008-5472 1538-7445 |
Statement of Responsibility: | Matja Rokavec, Werner Schroth, Sandra M.C. Amaral, Peter Fritz, Lydia Antoniadou, Damjan Glava, Wolfgang Simon, Matthias Schwab, Michel Eichelbaum and Hiltrud Brauch |
Abstract: | Tamoxifen therapy is a standard in the treatment of estrogen receptor (ER)-positive breast cancer; however, its efficacy varies widely among patients. In addition to interpatient differences in the tamoxifen-metabolizing capacity, there is growing evidence that crosstalk between ER and growth factor signaling contributes to tamoxifen resistance. We focused on TC21, a member of the Ras superfamily, to investigate the influence of the TC21 –582C>T promoter polymorphism on TC21 expression and treatment outcome. Immunohistochemical analyses of breast tumors revealed a higher TC21 expression in ER-negative compared with ER-positive tumors. Expression in ER-positive tumors was higher in carriers of the T allele in an allele dose–dependent manner. Quantitative real-time PCR analyses showed that TC21 mRNA expression is decreased after transfection of ER in ER-negative breast cancer cells MDA-MB-231, UACC893, and BT-20. In MCF7 ER-positive cells, TC21 expression decreased with 17β-estradiol treatment and increased after treatment with tamoxifen metabolites, 4-OH-tamoxifen, or endoxifen. In patients treated with adjuvant mono tamoxifen, high cytoplasmic TC21 tumor expression or the carriership of the –582T allele conferred increased recurrence rates [n = 45: hazard ratio (HR), 3.06; 95% confidence interval (95% CI), 1.16–8.05; n = 206: HR, 1.79; 95% CI, 1.08–3.00, respectively]. A combined analysis with the data of the known tamoxifen predictor CYP2D6 showed an improvement of outcome prediction compared with CYP2D6 or TC21 genotype status alone (per mutated gene HR, 2.35; 95% CI, 1.34–4.14). Our functional and patient-based results suggest that the TC21 –582C>T polymorphism improves prediction of tamoxifen treatment outcome in breast cancer. |
Keywords: | breast cancer tamoxifen TC21 |
Rights: | ©2008 American Association for Cancer Research. |
DOI: | 10.1158/0008-5472.CAN-08-0247 |
Published version: | http://dx.doi.org/10.1158/0008-5472.can-08-0247 |
Appears in Collections: | Aurora harvest 5 Pharmacology publications |
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