Clinical implications for loss or diminution of expression of Raf-1 kinase inhibitory protein and its phosphorylated form in ductal breast cancer.
Clinical implications for loss or diminution of expression of Raf-1 kinase inhibitory protein and its phosphorylated form in ductal breast cancer.
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发表时间：
2013-11
影响因子：
5.3
通讯作者：
F. Al-Mulla;M. Bitar;J. Thiery;Tan Tuan Zea;D. Chatterjee;Lindsay Bennett;Sungdae Park;J. Edwards-J.-Edwa
中科院分区：
文献类型：
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作者：
F. Al-Mulla;M. Bitar;J. Thiery;Tan Tuan Zea;D. Chatterjee;Lindsay Bennett;Sungdae Park;J. Edwards-J.-Edwa
RAF激酶抑制蛋白(RKIP)是一种成熟的转移抑制蛋白，在侵袭性癌症中经常下调。RKIP及其磷酸化形式对乳腺癌无病生存(DFS)和其他临床病理参数的影响尚不清楚。为此，我们研究了RKIP在3个独立乳腺癌队列中的表达。在蛋白质水平上，总RKIP表达的缺失或降低与以高增殖指数、高级别和雌激素(ER)和孕激素受体表达降低为特征的大型肿瘤相关。在所有队列中，RKIP表达的缺失或减少与较短的DFS显著相关。此外，对可手术的浸润性导管癌进行多因素分析，发现p-RKIP完全缺失是一个独立的预后因素。我们首次发现ER部分地通过MTA3-Snail轴驱动RKIP的表达。与这一发现一致的是，我们发现，在mRNA水平上，RKIP在不同分子亚型中的表达存在显著差异，其中Lumina(ER+)亚型表达高水平的RKIP，而更具侵袭性的Claudin-low(ER-)亚型表达最低的RKIP表达水平。总之，RKIP或其磷酸化形式的表达缺失/减少与乳腺癌的无病生存率低有关。检测RKIP和p-RKIP的表达对该病的治疗和分型具有重要的预后价值。
Raf Kinase inhibitory protein (RKIP) is a well-established metastasis suppressor that is frequently downregulated in aggressive cancers. The impact of RKIP and its phosphorylated form on disease-free survival (DFS) and other clinicopathological parameters in breast cancer is yet to be discovered. To this end, we examined RKIP expression in 3 independent breast cancer cohorts. At the Protein level, loss or reduced total RKIP expression was associated with large-sized tumors characterized by high proliferative index, high-grade and diminished estrogen (ER) and progesterone receptor expression. Loss or diminution of RKIP expression was significantly associated with shorter DFS in all cohorts. Moreover, the complete loss of p-RKIP was an independent prognostic factor using multivariate analysis in operable invasive ductal breast cancer. We show for the first time that ER, partly, drives RKIP expression through MTA3-Snail axis. Consistent with this finding, we found that, at the mRNA level, RKIP expression varied significantly across the different molecular subtypes of breast cancer with the Luminal (ER+) subtype expressing high levels of RKIP and the more aggressive Claudin-low (ER-) subtype, which depicted the highest epithelial to mesenchymal transition (EMT) registered the lowest RKIP expression levels. In conclusion, loss of expression/diminution of RKIP or its phosphorylated form is associated with poor diseases-free survival in breast cancer. Determining the expression of RKIP and p-RKIP adds significant prognostic value to the management and subtyping of this disease.