Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression
Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression
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DOI：
10.1002/path.4022
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发表时间：
2012-08-01
影响因子：
7.3
通讯作者：
Bartlett, John M. S.
中科院分区：
文献类型：
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作者：
Spears, Melanie;Cunningham, Carrie A.;Bartlett, John M. S.
PI3K/Akt信号转导通路在肿瘤进展和细胞存活中发挥重要作用。在内分泌治疗的乳腺癌中，Akt激活与预后不良有关，而细胞质中Akt2的高水平与总生存率的提高有关。使用邻近结扎法（PLAs）测定Akt1和Akt2在福尔马林固定、石蜡包埋细胞系和乳腺癌原位肿瘤组织中异构体特异性激活（磷酸化）的定量表达水平。plaas在乳腺癌样本中表达总pAkt1和pAkt2。高水平的pAkt1与DRFS （HR: 1.45, 95% CI 1.141.83, p = 0.002）和OS （HR: 1.42, 95% CI 1.101.83, p = 0.007）降低相关。当PLA结果合并时，与其他患者相比，pAkt1水平高的患者只有DRFS （HR: 1.92, 95% CI 1.342.76, p = 0.005）和OS （HR: 1.94, 95% CI 1.322.86, p = 0.008）显著降低。使用pla来区分Akt1和Akt2的激活表明Akt1驱动早期乳腺癌的进展。在Akt1/Akt2都被激活的情况下，Akt2可能会起到逆转这种作用。使用pla，我们在FFPE乳腺癌样本中分别原位测量了Akt1和Akt2蛋白的激活。版权所有2012年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine-treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform-specific activation (phosphorylation) of Akt1 and Akt2 in formalin-fixed, paraffin-embedded cell lines and breast cancer tumour tissues in situ. PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.141.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.101.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.342.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.322.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.