Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada.
Hum Pathol. 2010 Dec;41(12):1657-63. doi: 10.1016/j.humpath.2010.04.015. Epub 2010 Aug 14.
Glycogen synthase kinase 3β, recently found to be functionally abnormal in various types of human disease, is negatively regulated by the PI3K/Akt signaling pathway. As Akt is constitutively activated in a subset of breast cancer, we hypothesized that glycogen synthase kinase 3β is inappropriately inactivated in these cases. In this study, we aimed to assess (1) the overall frequency of glycogen synthase kinase 3β inactivation in breast cancer; (2) whether there is an association between Akt activation and glycogen synthase kinase 3β inactivation; and (3) whether there is a correlation between glycogen synthase kinase 3β inactivation and various pathologic and clinical parameters. The phosphorylated form of glycogen synthase kinase 3β (pGSK-3β) and Akt (pAkt) were used as surrogate markers for glycogen synthase kinase 3β inactivation and Akt activation, respectively. Immunohistochemistry applied to paraffin-embedded tissues was used to assess 72 consecutive invasive mammary carcinomas, of which 50 were estrogen receptor positive. Overall, pGSK-3β and pAkt were positive in 34 (47.2%) and 35 (48.6%) cases, respectively. These 2 markers were significantly correlated with each other in the overall group and in the estrogen receptor-positive subgroup (P = .01 and .003, Spearman, respectively). Importantly, pGSK-3β, but not pAkt, significantly correlated a worse clinical outcome in this cohort (P = .004, log rank). In summary, evidence of glycogen synthase kinase 3β inactivation was found in approximately half of the invasive mammary carcinomas. Our data suggest that this abnormality is likely attributed to Akt activation and that glycogen synthase kinase 3β inactivation confers a worse clinical outcome.
糖原合酶激酶 3β（GSK3β）最近在多种人类疾病中被发现功能异常，其活性受到 PI3K/Akt 信号通路的负向调节。由于 Akt 在乳腺癌的一部分病例中持续激活，我们推测在这些病例中 GSK3β被异常失活。本研究旨在评估：（1）乳腺癌中 GSK3β失活的总体频率；（2）Akt 激活与 GSK3β失活之间是否存在关联；（3）GSK3β失活与各种病理和临床参数之间是否存在相关性。磷酸化糖原合酶激酶 3β（pGSK-3β）和磷酸化 Akt（pAkt）分别被用作 GSK3β失活和 Akt 激活的替代标志物。采用免疫组化方法检测 72 例连续的浸润性乳腺浸润癌，其中 50 例雌激素受体阳性。总体而言，pGSK-3β 和 pAkt 在 34 例（47.2%）和 35 例（48.6%）病例中呈阳性。这两个标志物在总人群和雌激素受体阳性亚组中均显著相关（P =.01 和.003，Spearman 相关）。重要的是，pGSK-3β（而非 pAkt）与该队列的更差临床结局显著相关（P =.004，log rank）。总之，在大约一半的浸润性乳腺浸润癌中发现了 GSK3β 失活的证据。我们的数据表明，这种异常可能归因于 Akt 激活，并且 GSK3β 失活预示着更差的临床结局。
