Abstract
BackgroundThe HER2-HER3 heterodimer significantly decreases survival in breast cancer patients. However, the prognostic value of HER2-HER3 overexpression remains unknown in gastric cancer (GC).MethodsThe expression levels of HER2, HER3, Akt, p-Akt, mTOR and p-mTOR were examined in specimens from 120 GC patients by immunohistochemistry and quantitative reverse transcription-PCR. The associations of HER proteins, PI3K/Akt/mTOR pathway-related proteins, clinicopathological features of GC, and overall survival (OS) were assessed. To comprehensively evaluate the prognostic values of pathway-related proteins, meta-analyses were conducted with STATA 11.0.ResultsHER2 overexpression was significantly associated with HER3 levels (P = 0.02). HER3 was highly expressed in gastric cancer tissues. High HER2 and HER3 levels were associated with elevated p-Akt and p-mTOR amounts (P < 0.05). Furthermore, HER2-HER3 co-expression was associated with high p-Akt and p-mTOR (P < 0.05) levels. Meanwhile, p-mTOR overexpression was tightly associated with differentiation, depth of invasion, lymph node metastasis, TNM stage and OS (P < 0.05). By meta-analyses, Akt, p-Akt, and mTOR levels were unrelated to clinicopathological characters. HER3 overexpression was associated with depth of invasion (OR = 2.39, 95%CI 1.62–3.54, P < 0.001) and lymph node metastasis (OR = 2.35, 95%CI 1.34–4.11, P = 0.003). Further, p-mTOR overexpression was associated with patient age, tumor location, depth of invasion (OR = 1.63, 95%CI 1.08–2.45, P = 0.02) and TNM stage (OR = 1.73, 95%CI 1.29–2.32, P < 0.001). In addition, HER2-HER3 overexpression corresponded to gradually shortened 5-year OS (P < 0.05), and significant relationships were shown among HER3, p-mTOR overexpression, and 1-, 3-, 5-year OS (P < 0.05).ConclusionsHER2-HER3 co-expression may potentially enhance mTOR phosphorylation. HER2-HER3 co-expression and p-mTOR are both related to the prognosis of GC patients.
Highlights
The HER2-HER3 heterodimer significantly decreases survival in breast cancer patients
Our results suggested that HER2-HER3 coexpression leads to the phosphorylation of Akt and mTOR, which resulted in worse prognosis and shorter overall survival (OS) through a mechanism dependent on activated mTOR (p-mTOR)
Expression levels of different target proteins in gastric cancer According to IHC results, HER2, HER3, Akt, p-Akt, mTOR and p-mTOR were differently expressed in GC tissue samples
Summary
The HER2-HER3 heterodimer significantly decreases survival in breast cancer patients. The prognosis of patients with advanced GC remains dismal even after surgery or radical resection; 5–year overall survival (OS) is low, with a median OS of less than 1 year [3, 4]. Molecular-targeted treatment for GC has attracted increasing attention. Several articles have described potential molecular targets for GC therapy, such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) [5]. EGFR is a member of the human epidermal growth factor receptor (HER) family. The HER family is composed of four members, including EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4 [6], and plays a key role in the pathogenesis of various human solid tumors, including breast, gastric and lung cancers [7]
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