Open Access

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

  • Authors:
    • Peter Grell
    • Pavel Fabian
    • Marta Khoylou
    • Lenka Radova
    • Ondrej Slaby
    • Roman Hrstka
    • Rostislav Vyzula
    • Marian Hajduch
    • Marek Svoboda
  • View Affiliations

  • Published online on: July 27, 2012     https://doi.org/10.3892/ijo.2012.1576
  • Pages: 1204-1212
  • Copyright: © Grell et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.
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October 2012
Volume 41 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Grell P, Fabian P, Khoylou M, Radova L, Slaby O, Hrstka R, Vyzula R, Hajduch M and Svoboda M: Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Int J Oncol 41: 1204-1212, 2012
APA
Grell, P., Fabian, P., Khoylou, M., Radova, L., Slaby, O., Hrstka, R. ... Svoboda, M. (2012). Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. International Journal of Oncology, 41, 1204-1212. https://doi.org/10.3892/ijo.2012.1576
MLA
Grell, P., Fabian, P., Khoylou, M., Radova, L., Slaby, O., Hrstka, R., Vyzula, R., Hajduch, M., Svoboda, M."Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab". International Journal of Oncology 41.4 (2012): 1204-1212.
Chicago
Grell, P., Fabian, P., Khoylou, M., Radova, L., Slaby, O., Hrstka, R., Vyzula, R., Hajduch, M., Svoboda, M."Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab". International Journal of Oncology 41, no. 4 (2012): 1204-1212. https://doi.org/10.3892/ijo.2012.1576