Phospho-PRAS40Thr246 predicts trastuzumab response in patients with HER2-positive metastatic breast cancer
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- Published online on: November 28, 2014 https://doi.org/10.3892/ol.2014.2744
- Pages: 785-789
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Abstract
Resistance to trastuzumab is frequently observed during the treatment of patients with human epidermal growth factor 2 (HER2)‑positive metastatic breast cancers. The aim of the present study was to determine if the phosphorylated proline‑rich Akt substrate of 40 kDa (phospho‑PRAS40Thr246), a novel biomarker for phosphoinositol‑3 kinase (PI3K) pathway activation, could predict the response of HER2‑positive metastatic breast cancers to treatment with trastuzumab. Formalin‑fixed, paraffin‑embedded tumor tissue samples were retrospectively collected from 55 trastuzumab‑treated patients. Next, the expression of phospho‑PRAS40Thr246 and phosphatase and tensin homolog (PTEN) was assessed by immunohistochemistry. In total, five common phosphoinositol‑3 kinase α catalytic subunit mutations, namely E542K, E545K, E545D, H1047R and H1047L, were identified by the amplification‑refractory mutation system, using the allele‑specific polymerase chain reaction. The activation of the PI3K pathway, as determined by low PTEN expression or the presence of oncogenic PIK3CA mutations, was observed in 49.1% (27 cases) of the 55 HER2‑positive metastatic breast cancer tissues. In total, 40% of the tumors were defined as being phospho‑PRAS40Thr246‑positive. Furthermore, the results revealed that phospho‑PRAS40Thr246 expression was associated with the PI3K pathway activation status and an increased risk of tumor progression in HER2‑positive metastatic breast cancer patients who had received trastuzumab‑based therapy. Therefore, phospho‑PRAS40Thr246 expression levels may reflect the PI3K pathway activation status and act as a biomarker for HER2‑amplified breast cancer patients who are unlikely to respond to trastuzumab‑based therapy.
