title: Endoplasmic reticulum stress induces secretion of high-mobility group proteins and is associated with tumor-infiltrating lymphocytes in triple-negative breast cancer.
abstract: BACKGROUND
  Although the prognostic and predictive significance of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC) have been shown, the cause of the TIL influx is unclear. Here, we investigated whether extracellular secretion of HMGN1 is associated with TIL influx, as well as increased endoplasmic reticulum stress (ERS), in human TNBC.
  
  
  METHODS
  We reviewed the slides of 767 patients with TNBC and evaluated the TIL levels. We also assessed the expression of HMGs and several ERS-associated molecules using immunohistochemical staining. Western blot analysis of human TNBC cell lines and pharmacological ERS inducers was used to determine if HMGN1 migrates from the nucleus to the extracellular space in response to ERS.
  
  
  RESULTS
  On immunohistochemical staining, either higher nuclear or cytoplasmic expression of both HMGB1 and HMGN1 was significantly associated with ERS. TILs showed a positive correlation with the cytoplasmic expression of the HMGs. Western blot analysis of TNBC cell lines showed that ERS induction resulted in the secretion of HMG proteins.
  
  
  CONCLUSIONS
  This is the first study to elucidate the associations among ERS, secretion of HMGs, and degree of TILs in TNBCs. Understanding the mechanisms of TIL influx will help in the development of effective immunotherapeutic agents for TNBC.
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: In Ah
authors: IA
authors: Park
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.|Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Sun-Hee
authors: SH
authors: Heo
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: In Hye
authors: IH
authors: Song
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.|Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Young-Ae
authors: YA
authors: Kim
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.|Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Hye Seon
authors: HS
authors: Park
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.|Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Won Seon
authors: WS
authors: Bang
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.|Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Suk Young
authors: SY
authors: Park
authors: Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: Jeong-Hyon
authors: JH
authors: Jo
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Hee Jin
authors: HJ
authors: Lee
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Gyungyub
authors: G
authors: Gong
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D024241:HMGN1 Protein / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D021381:Protein Transport; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000401:mortality
chemical_list: D024241:HMGN1 Protein
keywords: breast carcinoma; endoplasmic reticulum; high-mobility group protein; tumor-infiltrating lymphocytes