title: Clinical and biological significance of GSK-3β inactivation in breast cancer-an immunohistochemical study.
abstract: 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.
authors: Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada.
authors: Hanan
authors: H
authors: Armanious
authors: Jean
authors: J
authors: Deschenes
authors: Pascal
authors: P
authors: Gelebart
authors: Sunita
authors: S
authors: Ghosh
authors: John
authors: J
authors: Mackey
authors: Raymond
authors: R
authors: Lai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007124:Immunoenzyme Techniques; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D004791:Enzyme Inhibitors; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3