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A Polymorphism in the TC21 Promoter Associates with an Unfavorable Tamoxifen Treatment Outcome in Breast Cancer

Matja Rokavec^1,3,5, Werner Schroth^1,3, Sandra M.C. Amaral^1,3,6, Peter Fritz^1,3, Lydia Antoniadou^1,3, Damjan Glava⁵, Wolfgang Simon², Matthias Schwab^1,3,4, Michel Eichelbaum^1,3 and Hiltrud Brauch^1,3

¹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and ² Department of Gynecology, Robert Bosch Hospital, Stuttgart, Germany; ³ University of Tübingen and ⁴ Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany; ⁵ Department of Molecular Genetics, Institute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia; and ⁶ Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal

Requests for reprints: Hiltrud Brauch, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. Phone: 49-711-8101-3705; Fax: 49-711-85-92-95; E-mail: hiltrud.brauch{at}ikp-stuttgart.de.

Key Words: breast cancer • tamoxifen • TC21

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. [Cancer Res 2008;68(23):9799–808]