Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients

Abstract

Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p 5 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy. ' 2005 Wiley-Liss, Inc.

A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

“…These findings indicate that mTOR is an essential therapeutic target of the Akt pathway. It is notable that Akt has been previously thought to be involved in development of resistance to hormone therapy (Kirkegaard et al, 2005;Tokunaga et al, 2006). The association of the Akt-mTOR genes with poor prognosis was found in some but not all patient data sets examined, although it is not readily apparent that this reflects the different treatment regimens being represented among the various tumor profiling studies.…”

“…In tissuebased studies (e.g. references Bose et al, 2006;Tokunaga et al, 2006), Akt is often measured in its phosphorylated form, whereas here AKT1 mRNA was used as a surrogate for p-Akt. By Q1-Q2 enrichment analysis method (Tian et al, 2005) (results shown in Figure 2b), the set of genes induced in AKT1-Tg were co-expressed as a group with AKT1 mRNA in human breast tumors.…”

“…The Akt-mTOR signature genes predict poor prognosis in multiple breast cancer patient cohorts Previous studies have associated activation of the Akt-mTOR pathway in breast tumors with poor patient outcome (Bose et al, 2006;Tokunaga et al, 2006). In this study, the gene signatures of Akt-mTORdependent (RAD001-sensitive) and Akt-mTOR-independent (RAD001-insensitive) pathways were each examined for correlation to patient outcome.…”

“…The Kaplan-Meier analysis required that a decision be made for the cutoff point between high-risk and low-risk groups for comparison (previous studies indicated that on the order of 30% of breast tumors have Akt pathway deregulation (Bose et al, 2006;Tokunaga et al, 2006)). In addition to Kaplan-Meier, the average expression of the Akt, RAD001-sensitive genes was treated as a continuous variable by univariate Cox regression analysis.…”

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

“…The mechanisms behind enhanced Akt phosphorylation are several, including HER2 amplification, PI3K mutation and PTEN loss (4). Most results suggest that pAkt correlates with poor prognosis (6,7) and is associated with other aggressive prognostic factors, such as HER2-positivity and lymph node positive breast cancer (8). In a recent study, activated Akt1 was shown to drive progression in early breast cancers, whereas activated Akt2 may reverse this effect in cases where both Akt1 and Akt2 are activated (9).…”