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: Matjaz Rokavec, Werner Schroth, Sandra M C Amaral, Peter Fritz, Lydia Antoniadou, Damjan Glavac, Wolfgang Simon, Matthias Schwab, Michel Eichelbaum, Hiltrud Brauch
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 23 Pg. 9799-808 (Dec 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 19047159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• DNA, Neoplasm
• Estrogen Receptor alpha
• Membrane Proteins
• RNA, Messenger
• Tamoxifen
• Cytochrome P-450 CYP2D6
• RRAS2 protein, human
• Monomeric GTP-Binding Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Antineoplastic Agents, Hormonal (pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Chemotherapy, Adjuvant
• Cytochrome P-450 CYP2D6 (genetics)
• DNA, Neoplasm (metabolism)
• Electrophoresis
• Estrogen Receptor alpha (metabolism)
• Female
• Genotype
• Humans
• Immunohistochemistry
• Membrane Proteins (biosynthesis, genetics, metabolism)
• Middle Aged
• Monomeric GTP-Binding Proteins (biosynthesis, genetics, metabolism)
• Polymorphism, Genetic
• RNA, Messenger (biosynthesis, genetics)
• Tamoxifen (pharmacology)