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 À582C>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 ERA in ER-negative breast cancer cells MDA-MB-231, UACC893, and BT-20. In MCF7 ERpositive cells, TC21 expression decreased with 17B-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 À582T 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 À582C>T polymorphism improves prediction of tamoxifen treatment outcome in breast cancer. [Cancer Res 2008;68(23):9799-808]

Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen

“…Specifically, high RRAS2 protein expression in breast tumor biopsies has been shown to correlate with a shorter time to relapse in tamoxifentreated patients, as does possession of a RRAS2 allele carrying the −582C→T RRAS2 promoter polymorphism present in ≈34% of European Caucasians (36). Our functional data support the case for RRAS2 playing a critical role in determining the response to tamoxifen and strengthens the argument for examining the functional effects of RRAS2 polymorphisms and how these relate to clinical outcome.…”

Automated Extraction of DNA and RNA from a Single Formalin-Fixed Paraffin-Embedded Tissue Section for Analysis of Both Single-Nucleotide Polymorphisms and mRNA Expression

“…The sample dropout rate in this investigation was Ͻ10% across all assays, which indicates that the automated extraction method provides genomic DNA of a quality comparable to that in similar studies in which archived FFPE tissue samples were used with manual DNA extraction procedures (5 ). We selected 5 genes known to harbor germline polymorphisms that have been reported to be related to breast cancer risk or disease progression (14,15 ), to functionally influence estrogen-receptor activity (NCOA3), or to be predictive for breast cancer tamoxifen outcome (16 ). Although our data showed very high concordance rates of genotypes between tumor and corresponding normal tissue, a few samples (1.1%) showed discordant alleles between paired samples.…”

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

“…Thus, the analysis of Rras2 À / À mice has revealed that this GTPase plays proactive roles during mammary gland development 18 . Furthermore, recent observations have indicated that R-RAS2 could contribute to tamoxifen resistance 19,20 , thus suggesting that the inactivation of this pathway could be beneficial for patients with oestrogen receptor-positive breast tumours. It should be noted, however, that the systemic loss of R-Ras2 leads to unexpected protumorigenic effects in the case of mouse neurofibroma 21 that, if reproduced in other cancer types and in humans, may limit the interest of anti-R-Ras2-based therapies.…”