Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy
Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy
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DOI：
10.1038/onc.2014.138
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发表时间：
2015-04-09
期刊：
影响因子：
8
通讯作者：
Ditzel, H. J.
中科院分区：
文献类型：
--
作者：
Elias, D.;Vever, H.;Ditzel, H. J.
为了阐明乳腺癌他莫昔芬耐药的分子机制，我们进行了基因阵列分析，并确定了366个基因的表达改变，在四个独特的他莫昔芬耐药（TamR）细胞系与亲本他莫昔芬敏感的MCF-7/S0.5细胞系。这些基因中的大多数在功能上与细胞增殖、死亡和基因表达的控制相关，并且包括FYN、PRKCA、ITPR 1、DPYD、DACH 1、林恩、GBP 1和PRLR。用FYN特异性小干扰RNA或SRC家族激酶抑制剂处理可降低TamR细胞系的细胞生长，而对MCF-7/S0.5细胞没有显著影响。此外，在亲本他莫昔芬敏感的MCF-7/S0.5细胞中过表达FYN导致对他莫昔芬治疗的敏感性降低，而在过表达FYN的MCF-7/S0.5细胞中敲低FYN恢复了对他莫昔芬的敏感性，证明了FYN在MCF-7细胞中的生长和存活促进功能。在TamR细胞中FYN敲低导致14-3-3和Cdc 25 A的磷酸化减少，表明FYN通过激活重要的细胞周期相关蛋白，可以克服他莫昔芬的抗增殖作用。对来自两组内分泌治疗的ER+乳腺癌患者（一组为晚期乳腺癌（N = 47），另一组为早期乳腺癌（N = 76））的原发性乳腺肿瘤中FYN的亚细胞定位进行评估，结果显示，在前者中，质膜相关FYN表达与较长的无进展生存期密切相关（P < 0.0002）。同样，在早期乳腺癌患者中，原发性乳腺肿瘤中FYN的膜相关表达与无转移（P < 0.04）和总生存率（P < 0.004）的增加显著相关，与肿瘤大小、分级或淋巴结状态无关。我们的研究结果表明，FYN在他莫昔芬耐药中具有重要作用，其在乳腺肿瘤细胞中的亚细胞定位可能是乳腺癌内分泌治疗反应的重要新生物标志物。
To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, whereas knockdown of FYN in the FYN-overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth-and survival-promoting function of FYN in MCF-7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N = 47) and the other with early disease (N = 76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P < 0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P < 0.04) and overall (P < 0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.