Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer
Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer
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DOI：
10.1007/s10549-008-0125-z
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发表时间：
2009-07-01
影响因子：
3.8
通讯作者：
Berns, Els M. J. J.
中科院分区：
文献类型：
--
作者：
Jansen, Maurice P. H. M.;Ruigrok-Ritstier, Kirsten;Berns, Els M. J. J.
目的 在我们的微阵列分析中，我们观察到对一线他莫昔芬治疗耐药的患者的雌激素受体 (ER) 阳性乳腺肿瘤中七缺同源物 2 (SIAH2) 水平较低。本研究的目的是评估 SIAH2 的 (a) 预测/预后价值，以及 (b) 在内分泌治疗耐药中的功能作用。患者和方法 使用定量实时 PCR (qRT-PCR) 测量 1205 个原发性乳腺肿瘤标本中的 SIAH2 表达，并将其与疾病结果相关。 SIAH2 的功能作用在人乳腺癌细胞系 ZR-75-1、ZR/HERc 和 MCF7 中得到确定。用雌激素（E2）、抗雌激素ICI164.384或表皮生长因子（EGF）处理细胞系。此外，在沉默SIAH2表达后，用ICI164.384处理MCF7。结果 SIAH2 对 603 名未接受辅助全身治疗的淋巴结阴性患者没有预后作用。在 235 名复发性疾病患者的 ER 阳性肿瘤的多变量分析中，SIAH2 作为连续变量，显着预测一线他莫昔芬治疗失败（OR = 1.48；P = 0.05）和无进展生存期（PFS）（HR = 0.79；P = 0.007）。此外，在接受他莫昔芬辅助治疗的原发性乳腺癌患者中，SIAH2 预测无转移生存期 (MFS)（HR = 0.73；P = 0.005）。体外实验表明，与模拟沉默细胞相比，MCF7 细胞中的 SIAH2 沉默会导致对 ICI164.384 治疗的抵抗（P = 0.008）。有趣的是，在转染 EGFR (ZR/HERc) 的 ZR 细胞中，E2 诱导 SIAH2 表达，但 EGF 下调 SIAH2 表达。结论 在原发性乳腺肿瘤标本以及体外，低 SIAH2 水平与内分泌治疗耐药相关。此外，SIAH2的表达显示出E2和EGF的相反调节。
Purpose In our microarray analysis we observed that Seven-in-Absentia Homolog 2 (SIAH2) levels were low in estrogen receptor (ER) positive breast tumors of patients resistant to first-line tamoxifen therapy. The aim of this study was to evaluate SIAH2 for its (a) predictive/prognostic value, and (b) functional role in endocrine therapy resistance. Patients and methods SIAH2 expression was measured with quantitative Real-Time-PCR (qRT-PCR) in 1205 primary breast tumor specimens and related to disease outcome. The functional role of SIAH2 was determined in human breast cancer cell lines ZR-75-1, ZR/HERc, and MCF7. Cell lines were treated with estrogen (E2), anti-estrogen ICI164.384 or epidermal growth factor (EGF). Moreover, MCF7 was treated with ICI164.384 after silencing SIAH2 expression. Results SIAH2 was not prognostic in 603 lymph node negative patients who had not received adjuvant systemic therapy. In multivariate analysis of ER-positive tumors of 235 patients with recurrent disease, SIAH2 as continuous variable, significantly predicted first-line tamoxifen treatment failure (OR = 1.48; P = 0.05) and progression-free survival (PFS) (HR = 0.79; P = 0.007). Furthermore, in primary breast cancer patients treated with adjuvant tamoxifen, SIAH2 predicted metastasis-free survival (MFS) (HR = 0.73; P = 0.005). In vitro experiments showed that SIAH2 silencing in MCF7 cells resulted in resistance to ICI164.384-treatment when compared with mock silenced cells (P = 0.008). Interestingly, in ZR cells transfected with EGFR (ZR/HERc), SIAH2 expression was induced by E2 but downregulated by EGF. Conclusion In primary breast tumor specimens as well as in vitro low SIAH2 levels associated with resistance to endocrine therapy. Moreover, SIAH2 expression showed an opposite regulation by E2 and EGF.