Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients

Abstract

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.

Figure 1

Representative immunostaining of Akt-1 (A) (200×) and pAkt (B) (400×), note the arrowheads indicating positive staining in the cytoplasm of malignant cells.

Figure 2

(A) Kaplan–Meier curves comparing survival among pAkt negative patients in comparison with pAkt positive group (P=0.07 by Cox proportional hazard model and P=0.03 by Gehan's generalized Wilcoxon test). (B) pAkt/SPF subgroups. The combined variable was scored as: 0 (SPF-/pAkt-); 1 (SPF+/pAkt-); 2 (SPF-/pAkt+); 3 (SPF+/pAkt+). According to this order, the risk of developing distant recurrence increased gradually with a rate ratio of 1.8 (Cox proportional hazard regression, P=0.017). Distant recurrence-free survival rates at 6 years were of 93, 88, 69 and 47% respectively for each subgroup. (C) Kaplan–Meier curves based on pAkt and nodal status. The combined variable was scored as: 0 (node-/pAkt-); 1 (node-/pAkt+); 2 (node+/pAkt-; 3 (node+/pAkt+). According to this order, the risk of developing distant recurrence increased gradually with a rate ratio of 2.5 (Cox proportional hazard regression P=0.001). Distant recurrence-free survival rates at 6 years were 100, 85, 81 and 59% respectively for each subgroup. In the lymph node negative group there were two recurrences; both belonged to pAkt+ subgroup.