Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab

Abstract

Trastuzumab is effective in about half of HER2-positive breast cancer patients. The PI3K/Akt signalling pathway plays an important role in the process of primary and secondary resistance to anti-HER2 targeted therapy. We evaluated the relationship between expression, activation and subcellular localization of selected Akt isoforms and response to trastuzumab-based anti-HER2 targeted therapy in patients with HER2-positive metastatic breast cancer. Seventy-four women with verified HER2-positive breast cancer were treated with trastuzumab for metastatic disease. Immunohistochemistry was used to evaluate Akt1, Akt2, pAkt Thr308 and pAkt Ser473 expression. For pAkt, cytoplasmic and nuclear fractions were assessed separately. Even though Akt isoforms were expressed in the majority of tumours, activated Akt (pAkt) was present in the cytoplasm only and not in the nucleus in >20% of tumours, and there was no pAkt at all in another 7–13% of tumours. Patients whose tumours showed strong Akt2 expression and had pAkt (pAkt-Thr308 and/or pAkt-Ser473) detectable in the cytoplasm as well as nucleus (n+c), exhibited improved time to progression (TTP) and overall survival from the initiation of trastuzumab therapy (OSt). Patients with tumours with strong Akt2 and pAkt Thr308 (n+c) had superior TTP (17.0 vs. 7.6 months, P=0.024; HR 0.52) and OSt (51.8 vs. 16.8 months, P=0.0009; HR 0.34) compared to other tumours. Similar results were found for strong Akt2 and pAkt Ser473 (n+c): TTP 13.1 vs. 7.2 months (P=0.085, HR 0.62) and OSt 50.8 vs. 17.0 months (P=0.009; HR 0.45). This study is the first to prove the significance of Akt kinase isoform, activity and compartmentalization for the prediction of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer.

Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate

“…We and others have shown that p473 Akt and p397 FAK co-localize at the invasive front of experimental mammary tumors and we found that this phenotype is lost if ECM cross-linking and stiffening is prevented (1,47). Here we determined that ECM stiffness mediates the localization and levels of these signaling molecules at the invasive front by activating vinculin.…”

The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

“…In our study of human tumors, AKT1 mRNA expression correlated with both ER status and PIPP expression and was significantly decreased in triple negative breast cancers. Several other studies, however, have reported no correlation between AKT1 mRNA or protein expression and ER status (Creighton, 2007;Grell et al, 2012;Stå l et al, 2003), although pAKT1 levels were reported as higher in ER + than ER À tumors (Gershtein et al, 2007). In addition, increased AKT1 kinase activity has been reported in 45% of primary breast cancers (Sun et al, 2001).…”

AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins

“…demonstrated that AKT2 and pAKT (pSer473AKT) levels were associated with a lower distant recurrence rate. In the same line, Grell et al 45. showed that AKT2 expression and concurrent presence of pAKT (pThr308AKT and/or pSer473AKT) linked to better outcome in HER2 + metastatic patients treated with Trastuzumab.…”

“…Recent studies that have associated AKT expression with cancer prognosis showed some contradictory results depending on the characteristics of the population evaluated and the technical approach454647. Pereira et al 47.…”