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.
Keywords: phosphoinositol-3 kinase; phosphorylation; progression; proline-rich Akt substrate of 40 kDa; trastuzumab resistance.