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

BMC Cancer

Zeng-Quan Yang⁴  Stephen Ethier¹  Kezhong Zhang⁷  Ze Zheng⁸  Judith Abrams⁵  Rouba Ali-Fehmi²  Seema Sethi⁹  Xiaogang Wang⁶  Gang Liu⁶  Guohui Wang³ 

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

[2]Department of Pathology, Wayne State University, Detroit, MI, 48201, USA

[3]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

[4]Department of Oncology, Wayne State University, Detroit, MI, 48201, USA

[5]Biostatistics Core of the Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

[6]Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

[7]Department of Immunology and Microbiology, Wayne State University, Detroit, MI, 48201, USA

[8]Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA

[9]Biorepository Core, Wayne State University, Detroit, MI, 48201, USA

关键词: ERLIN2;    Endoplasmic reticulum;    Breast cancer;    Gene amplification;   

Others  :  1080382
DOI  :  10.1186/1471-2407-12-225

 received in 2011-11-28, accepted in 2012-05-14,  发布年份 2012

【 摘 要 】

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

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Luo J, Solimini NL, Elledge SJ: Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009, 136(5):823-837.
• [2]Solimini NL, Luo J, Elledge SJ: Non-oncogene addiction and the stress phenotype of cancer cells. Cell 2007, 130(6):986-988.
• [3]Yang ZQ, Streicher KL, Ray ME, Abrams J, Ethier SP: Multiple interacting oncogenes on the 8p11-p12 amplicon in human breast cancer. Cancer Res 2006, 66(24):11632-11643.
• [4]Gelsi-Boyer V, Orsetti B, Cervera N, Finetti P, Sircoulomb F, Rouge C, Lasorsa L, Letessier A, Ginestier C, Monville F, et al.: Comprehensive profiling of 8p11-12 amplification in breast cancer. Molecular cancer research: MCR 2005, 3(12):655-667.
• [5]Garcia MJ, Pole JC, Chin SF, Teschendorff A, Naderi A, Ozdag H, Vias M, Kranjac T, Subkhankulova T, Paish C, et al.: A 1 Mb minimal amplicon at 8p11-12 in breast cancer identifies new candidate oncogenes. Oncogene 2005, 24(33):5235-5245.
• [6]Yang ZQ, Albertson D, Ethier SP: Genomic organization of the 8p11-p12 amplicon in three breast cancer cell lines. Cancer Genet Cytogenet 2004, 155(1):57-62.
• [7]Kwek SS, Roy R, Zhou H, Climent J, Martinez-Climent JA, Fridlyand J, Albertson DG: Co-amplified genes at 8p12 and 11q13 in breast tumors cooperate with two major pathways in oncogenesis. Oncogene 2009.
• [8]Ron D, Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007, 8(7):519-529.
• [9]Zhang K, Kaufman RJ: From endoplasmic-reticulum stress to the inflammatory response. Nature 2008, 454(7203):455-462.
• [10]Zhang K, Kaufman RJ: Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivo. Methods Enzymol 2008, 442:395-419.
• [11]Schroder M, Kaufman RJ: ER stress and the unfolded protein response. Mutat Res 2005, 569(1–2):29-63.
• [12]Dong D, Ni M, Li J, Xiong S, Ye W, Virrey JJ, Mao C, Ye R, Wang M, Pen L, et al.: Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res 2008, 68(2):498-505.
• [13]Pyrko P, Schonthal AH, Hofman FM, Chen TC, Lee AS: The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 2007, 67(20):9809-9816.
• [14]Daneshmand S, Quek ML, Lin E, Lee C, Cote RJ, Hawes D, Cai J, Groshen S, Lieskovsky G, Skinner DG, et al.: Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum Pathol 2007, 38(10):1547-1552.
• [15]Fu Y, Li J, Lee AS: GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res 2007, 67(8):3734-3740.
• [16]Hetz C: The UPR as a survival factor of cancer cells: More than folding proteins? Leuk Res 2009.
• [17]Ran Y, Hu H, Hu D, Zhou Z, Sun Y, Yu L, Sun L, Pan J, Liu J, Liu T, et al.: Derlin-1 is overexpressed on the tumor cell surface and enables antibody-mediated tumor targeting therapy. Clin Cancer Res 2008, 14(20):6538-6545.
• [18]Virrey JJ, Dong D, Stiles C, Patterson JB, Pen L, Ni M, Schonthal AH, Chen TC, Hofman FM, Lee AS: Stress chaperone GRP78/BiP confers chemoresistance to tumor-associated endothelial cells. Molecular cancer research: MCR 2008, 6(8):1268-1275.
• [19]Moenner M, Pluquet O, Bouchecareilh M, Chevet E: Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 2007, 67(22):10631-10634.
• [20]Wang G, Yang ZQ, Zhang K: Endoplasmic reticulum stress response in cancer: molecular mechanism and therapeutic potential. Am J Transl Res 2010, 2(1):65-74.
• [21]Tsai YC, Weissman AM: The Unfolded Protein Response, Degradation from Endoplasmic Reticulum and Cancer. Genes Cancer 2010, 1(7):764-778.
• [22]Healy SJ, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A: Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol 2009, 625(1–3):234-246.
• [23]Rutkowski DT, Hegde RS: Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 2010, 189(5):783-794.
• [24]Yang ZQ, Imoto I, Fukuda Y, Pimkhaokham A, Shimada Y, Imamura M, Sugano S, Nakamura Y, Inazawa J: Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines. Cancer Res 2000, 60(17):4735-4739.
• [25]Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, et al.: A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal , 3(106):ra7.
• [26]Tirasophon W, Lee K, Callaghan B, Welihinda A, Kaufman RJ: The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev 2000, 14(21):2725-2736.
• [27]Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH: Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 2003, 4(4):321-329.
• [28]Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, et al.: The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J 2011, 30(7):1357-1375.
• [29]Yang ZQ, Moffa AB, Haddad R, Streicher KL, Ethier SP: Transforming properties of TC-1 in human breast cancer: interaction with FGFR2 and beta-catenin signaling pathways. Int J Cancer 2007, 121(6):1265-1273.
• [30]Ali-Fehmi R, Che M, Khalifeh I, Malone JM, Morris R, Lawrence WD, Munkarah AR: The effect of cyclooxygenase-2 expression on tumor vascularity in advanced stage ovarian serous carcinoma. Cancer 2003, 98(7):1423-1429.
• [31]Ray ME, Yang ZQ, Albertson D, Kleer CG, Washburn JG, Macoska JA, Ethier SP: Genomic and expression analysis of the 8p11-12 amplicon in human breast cancer cell lines. Cancer Res 2004, 64(1):40-47.
• [32]Forozan F, Veldman R, Ammerman CA, Parsa NZ, Kallioniemi A, Kallioniemi OP, Ethier SP: Molecular cytogenetic analysis of 11 new breast cancer cell lines. Br J Cancer 1999, 81(8):1328-1334.
• [33]Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al.: The landscape of somatic copy-number alteration across human cancers. Nature 2010, 463(7283):899-905.
• [34]Pearce MM, Wang Y, Kelley GG, Wojcikiewicz RJ: SPFH2 mediates the endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors and other substrates in mammalian cells. J Biol Chem 2007, 282(28):20104-20115.
• [35]Pearce MM, Wormer DB, Wilkens S, Wojcikiewicz RJ: An ER membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of IP3 receptors. J Biol Chem 2009.
• [36]Browman DT, Resek ME, Zajchowski LD, Robbins SM: Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. J Cell Sci 2006, 119(Pt 15):3149-3160.
• [37]Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K: A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 2003, 4(2):265-271.
• [38]Fujimoto T, Onda M, Nagai H, Nagahata T, Ogawa K, Emi M: Upregulation and overexpression of human X-box binding protein 1 (hXBP-1) gene in primary breast cancers. Breast Cancer 2003, 10(4):301-306.
• [39]Davies MP, Barraclough DL, Stewart C, Joyce KA, Eccles RM, Barraclough R, Rudland PS, Sibson DR: Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer. Int J Cancer 2008, 123(1):85-88.
• [40]Zhang K, Wong HN, Song B, Miller CN, Scheuner D, Kaufman RJ: The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest 2005, 115(2):268-281.
• [41]Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, et al.: A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal 2010, 3(106):ra7.
• [42]Pole JC, Courtay-Cahen C, Garcia MJ, Blood KA, Cooke SL, Alsop AE, Tse DM, Caldas C, Edwards PA: High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation. Oncogene 2006, 25(41):5693-5706.
• [43]Haverty PM, Fridlyand J, Li L, Getz G, Beroukhim R, Lohr S, Wu TD, Cavet G, Zhang Z, Chant J: High-resolution genomic and expression analyses of copy number alterations in breast tumors. Genes Chromosomes Cancer 2008, 47(6):530-542.
• [44]Holland DG, Burleigh A, Git A, Goldgraben MA, Perez-Mancera PA, Chin SF, Hurtado A, Bruna A, Ali HR, Greenwood W, et al.: ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium. EMBO Mol Med 2011, 3(3):167-180.
• [45]Sircoulomb F, Nicolas N, Ferrari A, Finetti P, Bekhouche I, Rousselet E, Lonigro A, Adelaide J, Baudelet E, Esteyries S, et al.: ZNF703 gene amplification at 8p12 specifies luminal B breast cancer. EMBO Mol Med 2011, 3(3):153-166.
• [46]Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, et al.: Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 2006, 10(6):529-541.
• [47]Woods Ignatoski KM, Dziubinski ML, Ammerman C, Ethier SP: Cooperative interactions of HER-2 and HPV-16 oncoproteins in the malignant transformation of human mammary epithelial cells. Neoplasia 2005, 7(8):788-798.
• [48]Behbod F, Kittrell FS, LaMarca H, Edwards D, Kerbawy S, Heestand JC, Young E, Mukhopadhyay P, Yeh HW, Allred DC, et al.: An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ. Breast Cancer Res 2009, 11(5):R66. BioMed Central Full Text
• [49]Browman DT, Hoegg MB, Robbins SM: The SPFH domain-containing proteins: more than lipid raft markers. Trends Cell Biol 2007, 17(8):394-402.
• [50]Jo Y, Sguigna PV, DeBose-Boyd RA: Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 2011, 286(17):15022-15031.
• [51]Shajahan AN, Riggins RB, Clarke R: The role of X-box binding protein-1 in tumorigenicity. Drug News Perspect 2009, 22(5):241-246.
• [52]Shen X, Zhang K, Kaufman RJ: The unfolded protein response–a stress signaling pathway of the endoplasmic reticulum. J Chem Neuroanat 2004, 28(1–2):79-92.
• [53]Hetz C, Martinon F, Rodriguez D, Glimcher LH: The Unfolded Protein Response: integrating Stress Signals Through the Stress Sensor IRE1{alpha}. Physiol Rev 2011, 91(4):1219-1243.
• [54]Soule HD, Maloney TM, Wolman SR, et al.: Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 1990, 50:6075-86.
• [55]Ethier SP, Mahacek ML, Gullick WJ, Frank TS, Weber BL: Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res 1993, 53:627-35.
• [56]Ethier SP, Kokeny KE, Ridings JW, Dilts CA: erbB family receptor expression and growth regulation in a newly isolated human breast cancer cell line. Cancer Res 1996, 56:899-907.
• [57]Forozan F, Veldman R, Ammerman CA, et al.: Molecular cytogenetic analysis of 11 new breast cancer cell lines. Br J Cancer 1999, 81:1328-34.
• [58]Ray ME, Yang ZQ, Albertson D, et al.: Genomic and expression analysis of the 8p11-12 amplicon in human breast cancer cell lines. Cancer Res 2004, 64:40-7.