Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen
Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen
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DOI：
10.1186/bcr2820
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发表时间：
2011-01-01
影响因子：
7.4
通讯作者：
Jirstrom, Karin
中科院分区：
文献类型：
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作者：
Brennan, Donal J.;Laursen, Henriette;Jirstrom, Karin
我们之前报道了肿瘤特异性3-羟基-3-甲基谷胱甘肽辅酶A还原酶（HMG-CoAR）表达与乳腺癌良好预后之间的关联。本研究检验了HMG-CoAR表达与他莫昔芬反应的预测价值。方法：采用western blotting和PCR方法分析HMG-CoAR蛋白和RNA在三苯氧胺耐药细胞系模型中的表达。在先前发表的一项基因表达研究（队列I）中，我们检测了155个经他莫昔芬治疗的乳腺肿瘤中HMG-CoAR mRNA的表达。在422名II期绝经前乳腺癌患者中检测了HMG-CoAR蛋白表达，这些患者之前参加了一项随机对照试验，比较了2年的他莫昔芬和无全身辅助治疗（队列II）。采用Kaplan-Meier分析和Cox比例风险模型评估无复发生存（RFS）风险和HMG-CoAR表达对他莫昔芬反应的影响。结果：他莫昔芬耐药的MCF7-LCC9细胞中HMG-CoAR蛋白和RNA的表达比他莫昔芬敏感的亲本细胞系降低。在他莫昔芬治疗后复发的肿瘤中，HMG-CoAR mRNA表达降低（P < 0.001），是队列I中RFS的独立预测因子（风险比= 0.63,P = 0.009）。在队列II中，佐剂他莫昔芬增加了hmg - coar阳性肿瘤的RFS （P = 0.008）。多因素Cox回归分析显示，HMG-CoAR是队列II中RFS改善的独立预测因子（风险比= 0.67,P = 0.010），亚组分析显示，雌激素受体（ER）阳性患者的RFS改善仍然存在（风险比= 0.65,P = 0.029）。多因素相互作用分析显示，他莫昔芬疗效与HMG-CoAR表达相关（P = 0.05）。他莫昔芬应答分析显示，er阳性/HMG-CoAR肿瘤患者对他莫昔芬的应答显著（P = 0.010）， er阳性或HMG-CoAR阳性肿瘤患者对他莫昔芬的应答显著（P = 0.035）。根据ER和HMG-CoAR状态分层显示，治疗组ER阳性/HMG-CoAR阳性肿瘤的RFS优于ER阳性/HMG-CoAR阴性肿瘤（P = 0.033）；然而，这种效应在对照组中消失（P = 0.138），这表明HMG-CoAR预测了他莫昔芬的反应。结论：HMG CoAR表达是er阳性和er阴性疾病对他莫昔芬反应的预测因子。表达ER或HMG-CoAR的绝经前肿瘤患者对辅助他莫昔芬有反应。
Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined.Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response.Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response.Conclusions: HMG CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.