Endoplasmic reticulum stress induces secretion of high-mobility group proteins and is associated with tumor-infiltrating lymphocytes in triple-negative breast cancer
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In Ah Park1,*, Sun-Hee Heo1,2,*, In Hye Song1, Young-Ae Kim1,2, Hye Seon Park1,2, Won Seon Bang1,2, Suk Young Park1,2, Jeong-Hyon Jo3, Hee Jin Lee1,**, Gyungyub Gong1,**
1Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
2Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
3Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
*Authors share co-first authorship
**Authors share co-corresponding authorship
Hee Jin Lee, email: firstname.lastname@example.org
Gyungyub Gong, email: email@example.com
Keywords: breast carcinoma, tumor-infiltrating lymphocytes, endoplasmic reticulum, high-mobility group protein
Received: April 23, 2016 Accepted: July 19, 2016 Published: August 2, 2016
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.
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