Author/Editor     Rokavec, Matjaž; Schroth, Werner; Amaral, Sandra M; Fritz, Peter; Antoniadou, Lydia; Glavač, Damjan; Simon, Wolfang; Schwab, Matthias; Eichelbaum, Michel; Brauch, Hiltrud
Title     A polymorphism in the TC21 promoter associates with an unfavorable tamoxifen treatment outcome in breast cancer
Type     članek
Source     Cancer Res
Vol. and No.     Letnik 68, št. 23
Publication year     2008
Volume     str. 9799-808
Language     eng
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 ERalpha in ER-negative breast cancer cells MDA-MB-231, UACC893, and BT-20. In MCF7 ER-positive cells, TC21 expression decreased with 17beta-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.
Descriptors     ADULT
AGED
AGED, 80 AND OVER
ALLELES
ANTINEOPLASTIC AGENTS, HORMONAL
BREAST NEOPLASMS
CHEMOTHERAPY, ADJUVANT
CYTOCHROME P-450 CYP2D6
DNA, NEOPLASM
ELECTROPHORESIS
GENOTYPE
IMMUNOHISTOCHEMISTRY
MEMBRANE PROTEINS
RNA, MESSENGER
TAMOXIFEN