UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Breast Cancer Res. 2011 Jan 31;13(1):R12. doi: 10.1186/bcr2820.
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.
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.
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.
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.
我们之前报道过肿瘤特异性 3-羟基-3-甲基戊二酰基辅酶 A 还原酶（HMG-CoAR）表达与乳腺癌预后良好之间存在关联。在这里，我们研究了 HMG-CoAR 表达与他莫昔芬反应之间的预测价值。
使用 Western blot 和 PCR 分析了他莫昔芬耐药 MCF7-LCC9 细胞系模型中的 HMG-CoAR 蛋白和 RNA 表达。在之前发表的基因表达研究（队列 I）中，检查了 155 例接受他莫昔芬治疗的乳腺癌肿瘤的 HMG-CoAR mRNA 表达。在 422 例接受过随机对照试验的绝经前 II 期乳腺癌患者中检测了 HMG-CoAR 蛋白表达，该试验比较了 2 年他莫昔芬治疗与无全身辅助治疗（队列 II）。使用 Kaplan-Meier 分析和 Cox 比例风险模型来估计无复发生存率（RFS）的风险和 HMG-CoAR 表达对他莫昔芬反应的影响。
与亲本敏感细胞系相比，他莫昔芬耐药 MCF7-LCC9 细胞中的 HMG-CoAR 蛋白和 RNA 表达降低。HMG-CoAR mRNA 表达在接受他莫昔芬治疗后复发的肿瘤中降低（P < 0.001），并且是队列 I 中 RFS 的独立预测因子（危险比= 0.63，P = 0.009）。在队列 II 中，辅助他莫昔芬增加了 HMG-CoAR 阳性肿瘤的 RFS（P = 0.008）。多变量 Cox 回归分析表明，HMG-CoAR 是队列 II 中 RFS 改善的独立预测因子（危险比= 0.67，P = 0.010），亚组分析显示，这在雌激素受体（ER）阳性患者中得到维持（危险比= 0.65，P = 0.029）。多变量交互分析表明，HMG-CoAR 表达与他莫昔芬疗效存在差异（P = 0.05）。对他莫昔芬反应的分析表明，ER 阳性/HMG-CoAR 阳性肿瘤的患者对他莫昔芬有明显的反应（P = 0.010），以及 ER 阳性或 HMG-CoAR 阳性肿瘤的患者（P = 0.035）。根据 ER 和 HMG-CoAR 状态分层表明，与 ER 阳性/HMG-CoAR 阴性肿瘤相比，ER 阳性/HMG-CoAR 阳性肿瘤在治疗组中的 RFS 得到改善（P = 0.033）；然而，在对照组中（P = 0.138），这种作用消失了，这表明 HMG-CoAR 预测了他莫昔芬的反应。
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 的绝经前患者对辅助他莫昔芬有反应。
