Activation of the PERK-eIF2α Pathway Is Associated with Tumor-infiltrating Lymphocytes in HER2-Positive Breast Cancer

Background: We evaluated endoplasmic reticulum stress and unfolded protein response (UPR) activation, as possible mechanisms for influx of tumor infiltrating lymphocytes (TILs), and the correlation between UPR activation and mammalian target of rapamycin (mTOR) pathway activation. Materials and Methods: TILs and the immunohistochemical expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic translation initiation factor 2 alpha (p-eIF2 alpha) and phosphorylated S6 (pS6) were evaluated in 447 human epidermal growth factor receptor 2 (HER2)-positive breast cancer tissues. Results: High expression of PERK, p-eIF2 alpha and pS6 was observed in 270 (60.4%), 259 (57.9%), and 187 (41.8%) cases, respectively, and was significantly associated with a high histological grade, high numbers of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. Conclusion: The results suggest endoplasmic reticulum stress and UPR activation as possible mechanisms for the influx of TILs in HER2-positive breast cancer. Evaluation of PERK and p-eIF2a expression might be important in identifying targets for cancer therapies in modulating endoplasmic reticulum stress.