Positive prognostic value of HER2-HER3 co-expression and p-mTOR in gastric cancer patients

Background: The HER2-HER3 heterodimer significantly decreases survival in breast cancer patients. However, the prognostic value of HER2-HER3 overexpression remains unknown in gastric cancer (GC). Methods: The 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. Results: HER2 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). Conclusions: HER2-HER3 co-expression may potentially enhance mTOR phosphorylation. HER2-HER3 co-expression and pmTOR are both related to the prognosis of GC patients.