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.


METHODS
TILs and the immunohistochemical expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic translation initiation factor 2α (p-eIF2α) 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-eIF2α 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.


CONCLUSIONS
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-eIF2α expression might be important in identifying targets for cancer therapies in modulating endoplasmic reticulum stress.
Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Joo Young
JY
Kim
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Sun-Hee
SH
Heo
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
In Hye
IH
Song
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
In Ah
IA
Park
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Young-Ae
YA
Kim
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Gyungyub
G
Gong
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea backlila@gmail.com.
Hee Jin
HJ
Lee
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology*; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000502:physiology*
D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C460640:EIF2AK3 protein, human
Breast cancer; HER2; PERK; p-eIF2α; pS6; tumor-infiltrating lymphocytes