title: A polymorphism in the TC21 promoter associates with an unfavorable tamoxifen treatment outcome in breast cancer.
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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and Department of Gynecology, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Rokavec
authors.forename: Werner
authors.initials: W
authors.lastname: Schroth
authors.forename: Sandra M C
authors.initials: SM
authors.lastname: Amaral
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.forename: Lydia
authors.initials: L
authors.lastname: Antoniadou
authors.forename: Damjan
authors.initials: D
authors.lastname: Glavac
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Simon
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004273:DNA, Neoplasm / Q000378:metabolism; D004586:Electrophoresis; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D012333:RNA, Messenger; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6; C087360:RRAS2 protein, human; D020559:Monomeric GTP-Binding Proteins