Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis.
BACKGROUND
Aberrant microenvironment and endoplasmic reticulum (ER) stress are associated with solid-tumor progression. Stress proteins, like heat shock proteins and glucose-regulated proteins, are frequently overexpressed in human tumors. It has been reported that derlin-1 is involved in ER stress response. In vitro studies have demonstrated that derlin-1 participates in the retrotranslocation of misfolded proteins from ER into the cytosol. Because the roles of derlin-1 in human cancer have not yet been characterized, we investigated the expression of derlin-1 in human breast carcinoma and whether it protected cancer cells against ER stress-induced apoptosis.


METHODS
Surgical specimens of human breast cancer and/or paired normal tissues from the same patients were collected for immunohistochemical and/or Western blot analysis with anti-human derlin-1 antibody. The expression of derlin-1 in human breast cancer cell lines was detected by reverse transcription-polymerase chain reaction or Western blot. A synthetic small interfering RNA against derlin-1 was introduced into breast cancer cells to inhibit derlin-1 expression. The effects of derlin-1 knockdown on ER stress-induced apoptosis were determined by flow cytometry analysis.


RESULTS
These analyses demonstrated that 66.7% of the breast carcinoma tissues expressed derlin-1, whereas derlin-1 was rarely expressed in normal mammary glands. The expression of derlin-1 in human breast carcinoma correlated with tumor grade and axillary lymph node metastasis. On examining the expression of derlin-1 in human breast cancer cell lines, we found that derlin-1 expression was enhanced by ER stress-inducing agents. Derlin-1 knockdown sensitized breast cancer cells to ER stress-induced apoptosis.


CONCLUSIONS
The observed derlin-1 overexpression in breast cancer, together with its function in relieving ER stress-induced apoptosis, suggests that regulation of the ER stress response pathway may be critical in the development and progression of breast cancer.
Wang
Jiao
J
Division of Signal Transduction and Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1 Ke Yuan 4 Lu, Chengdu, 610041, China.
Hua
Hui
H
Ran
Yuliang
Y
Zhang
Hongyin
H
Liu
Weiping
W
Yang
Zhihua
Z
Jiang
Yangfu
Y
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D013312:Stress, Physiological / Q000378:metabolism
C487709:DERL1 protein, human; D008565:Membrane Proteins