Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

被引:78
作者
Bièche, I
Girault, I
Urbain, E
Tozlu, S
Lidereau, R
机构
[1] Ctr Rene Huguenin, INSERM, E0017, Lab Oncogenet, F-92211 St Cloud, France
[2] Univ Paris 05, Fac Sci Pharmaceut & Biol, Genet Mol Lab, UPRES EA 3618, Paris, France
关键词
breast cancer; prognostic value; real-time RT-PCR quantification; tamoxifen xenobiotic-metabolizing enzyme expression;
D O I
10.1186/bcr784
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Introduction: Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. Methods: To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes ( 12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast ( and liver) tissues, and in estrogen receptor alpha (ERalpha)-negative and ERalpha-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERalpha-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. Results: Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes ( CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERalpha-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERalpha-positive breast tumors than in ERalpha-negative breast tumors. In the 97 ERalpha-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERalpha-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis ( P = 0.0013). Conclusions: Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an attractive candidate molecular predictor of antiestrogen responsiveness.
引用
收藏
页码:R252 / R263
页数:12
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