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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
Statement of
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
Rights: ©2008 American Association for Cancer Research.
DOI: 10.1158/0008-5472.CAN-08-0247
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