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Open Access Highly Accessed Research article

ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways

Guohui Wang128, Gang Liu1, Xiaogang Wang1, Seema Sethi36, Rouba Ali-Fehmi4, Judith Abrams37, Ze Zheng2, Kezhong Zhang125*, Stephen Ethier19 and Zeng-Quan Yang13*

Author Affiliations

1 Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

2 Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA

3 Department of Oncology, Wayne State University, Detroit, MI, 48201, USA

4 Department of Pathology, Wayne State University, Detroit, MI, 48201, USA

5 Department of Immunology and Microbiology, Wayne State University, Detroit, MI, 48201, USA

6 Biorepository Core, Wayne State University, Detroit, MI, 48201, USA

7 Biostatistics Core of the Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

8 Department of Medical Imaging and Interventional Radiology, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, China

9 Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, BEB 412, 68 President St, Charleston, SC 29425, USA

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BMC Cancer 2012, 12:225  doi:10.1186/1471-2407-12-225

Published: 8 June 2012

Abstract

Background

Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear.

Methods

We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A) using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER stress sensor IRE1α activity in the breast cancer cell lines to characterize the biological roles and molecular basis of the ERLIN2 in carcinogenesis. Finally, immunohistochemical staining was performed to detect ERLIN2 expression in normal and cancerous human breast tissues

Results

We found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein occurs in both luminal and Her2 subtypes of breast cancer. Gain- and loss-of-function approaches demonstrated that ERLIN2 is a novel oncogenic factor associated with the ER stress response pathway. The IRE1α/XBP1 axis in the ER stress pathway modulated expression of ERLIN2 protein levels in breast cancer cells. We also showed that over expression of ERLIN2 facilitated the adaptation of breast epithelial cells to ER stress by supporting cell growth and protecting the cells from ER stress-induced cell death.

Conclusions

ERLIN2 may confer a selective growth advantage for breast cancer cells by facilitating a cytoprotective response to various cellular stresses associated with oncogenesis. The information provided here sheds new light on the mechanism of breast cancer malignancy

Keywords:
Gene amplification; Breast cancer; Endoplasmic reticulum; ERLIN2