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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer

Authors: Wan-xin Peng, Jian-guo Huang, Liu Yang, Ai-hua Gong, Yin-Yuan Mo

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

The conversion from estrogen-dependent to estrogen-independent state of ER+ breast cancer cells is the key step to promote resistance to endocrine therapies. Although the crucial role of MAPK/ERK signaling pathway in estrogen-independent breast cancer cell growth is well established, the underlying mechanism is not fully understood.

Methods

In this study, we profiled lncRNA expression against a focused group of lncRNAs selected from lncRNA database. CRISPR/Cas9 was employed to knockout (KO) linc-RoR in MCF-7 cells, while rescue experiments were carried out to re-express linc-RoR in KO cells. Colony formation and MTT assays were used to examine the role of linc-RoR in estrogen-independent growth and tamoxifen resistance. Western blot and qRT-PCR were used to determine the change of protein and lncRNA levels, respectively. The expression of DUSP7 in clinical specimens was downloaded from Oncomine (www.​oncomine.​org) and the dataset from Kaplan-Meier Plotter (http://​kmplot.​com) was used to analyze the clinical outcomes in relation to DUSP7.

Results

We identified that linc-RoR functions as an onco-lncRNA to promote estrogen-independent growth of ER+ breast cancer. Under estrogen deprivation, linc-RoR causes the upregulation of phosphorylated MAPK/ERK pathway which in turn activates ER signaling. Knockout of linc-RoR abrogates estrogen deprivation-induced ERK activation as well as ER phosphorylation, whereas re-expression of linc-RoR restores all above phenotypes. Moreover, we show that the ERK-specific phosphatase Dual Specificity Phosphatase 7 (DUSP7), also known as MKP-X, is involved in linc-RoR KO-induced repression of MAPK/ERK signaling. Interestingly, linc-RoR KO increases the protein stability of DUSP7, resulting in repression of ERK phosphorylation. Clinical data analysis reveal that DUSP7 expression is lower in ER+ breast cancer samples than that in ER- breast cancer. Moreover, downregulation of DUSP7 expression is associated with poor patient survival.

Conclusion

Taken together, these results suggest that linc-RoR promotes estrogen-independent growth and activation of MAPK/ERK pathway of breast cancer cells by regulating the ERK-specific phosphatase DUSP7. Thus, this study might help not only in establishing a role for linc-RoR in estrogen-independent and tamoxifen resistance of ER+ breast cancer, but also suggesting a link between linc-RoR and MAPK/ERK pathway.
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Literature
1.
Kumler I, Knoop AS, Jessing CA, Ejlertsen B, Nielsen DL. Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant. ESMO Open. 2016;1:e000062.CrossRefPubMedPubMedCentral
2.
Gu G, Dustin D, Fuqua SA. Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment. Curr Opin Pharmacol. 2016;31:97–103.CrossRefPubMed
3.
Mancuso MR, Massarweh SA. Endocrine therapy and strategies to overcome therapeutic resistance in breast cancer. Curr Probl Cancer. 2016;
4.
Pritchard KI. Endocrine therapy: is the first generation of targeted drugs the last? J Intern Med. 2013;274:144–52.CrossRefPubMed
5.
Sachdeva M, Wu H, Ru P, Hwang L, Trieu V, Mo YY. MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene. 2011;30:822–31.CrossRefPubMed
6.
Zhang Y, Su H, Rahimi M, Tochihara R, Tang C. EGFRvIII-induced estrogen-independence, tamoxifen-resistance phenotype correlates with PgR expression and modulation of apoptotic molecules in breast cancer. Int J Cancer. 2009;125:2021–8.CrossRefPubMedPubMedCentral
7.
Daurio NA, Tuttle SW, Worth AJ, Song EY, Davis JM, Snyder NW, Blair IA, Koumenis C. AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor-Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment. Cancer Res. 2016;76:3295–306.CrossRefPubMedPubMedCentral
8.
Angus L, Beije N, Jager A, Martens JW, Sleijfer S. ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients. Cancer Treat Rev. 2016;52:33–40.CrossRefPubMed
9.
10.
Tang JY, Lee JC, Chang YT, Hou MF, Huang HW, Liaw CC, Chang HW. Long noncoding RNAs-related diseases, cancers, and drugs. ScientificWorldJournal. 2013;2013:943539.PubMedPubMedCentral
11.
Hayes EL, Lewis-Wambi JS. Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA. Breast Cancer Res. 2015;17:40.CrossRefPubMedPubMedCentral
12.
Xue X, Yang YA, Zhang A, Fong KW, Kim J, Song B, Li S, Zhao JC, Yu J. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 2016;35:2746–55.CrossRefPubMed
13.
Wu C, Luo J. Long Non-Coding RNA (lncRNA) Urothelial Carcinoma-Associated 1 (UCA1) Enhances Tamoxifen Resistance in Breast Cancer Cells via Inhibiting mTOR Signaling Pathway. Med Sci Monit. 2016;22:3860–7.CrossRefPubMedPubMedCentral
14.
Jain AK, Xi Y, McCarthy R, Allton K, Akdemir KC, Patel LR, Aronow B, Lin C, Li W, Yang L, Barton MC. LncPRESS1 Is a p53-Regulated LncRNA that Safeguards Pluripotency by Disrupting SIRT6-Mediated De-acetylation of Histone H3K56. Mol Cell. 2016;64:967–81.CrossRefPubMed
15.
Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, Garber M, Curran M, Onder T, Agarwal S, et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 2010;42:1113–7.CrossRefPubMedPubMedCentral
16.
Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, Peterson RT, Yeh JR, Joung JK. Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat Biotechnol. 2013;31:227–9.CrossRefPubMedPubMedCentral
17.
Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D, Lu Z, Bai C, Watabe K, Mo YY. The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage. Cell Res. 2013;23:340–50.CrossRefPubMed
18.
Huang J, Zhang A, Ho TT, Zhang Z, Zhou N, Ding X, Zhang X, Xu M, Mo YY. Linc-RoR promotes c-Myc expression through hnRNP I and AUF1. Nucleic Acids Res. 2016;44:3059–69.CrossRefPubMed
19.
Eades G, Wolfson B, Zhang Y, Li Q, Yao Y, Zhou Q. lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res. 2015;13:330–8.CrossRefPubMed
20.
Liu Q, Huang J, Zhou N, Zhang Z, Zhang A, Lu Z, Wu F, Mo YY. LncRNA loc285194 is a p53-regulated tumor suppressor. Nucleic Acids Res. 2013;41:4976–87.CrossRefPubMedPubMedCentral
21.
22.
Peng WX, Xiong EM, Ge L, Wan YY, Zhang CL, FY D, Xu M, Bhat RA, Jin J, Gong AH. Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells. Exp Cell Res. 2016;340:62–70.CrossRefPubMed
23.
24.
Ho TT, Zhou N, Huang J, Koirala P, Xu M, Fung R, Wu F, Mo YY. Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res. 2015;43:e17.CrossRefPubMed
25.
Wu F, Chiocca S, Beck WT, Mo YY. Gam1-associated alterations of drug responsiveness through activation of apoptosis. Mol Cancer Ther. 2007;6:1823–30.CrossRefPubMed
26.
Chen WC, Wang CY, Hung YH, Weng TY, Yen MC, Lai MD. Systematic Analysis of Gene Expression Alterations and Clinical Outcomes for Long-Chain Acyl-Coenzyme A Synthetase Family in Cancer. PLoS One. 2016;11:e0155660.CrossRefPubMedPubMedCentral
27.
Mohseni M, Cidado J, Croessmann S, Cravero K, Cimino-Mathews A, Wong HY, Scharpf R, Zabransky DJ, Abukhdeir AM, Garay JP, et al. MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers. Proc Natl Acad Sci U S A. 2014;111:17606–11.CrossRefPubMedPubMedCentral
28.
Coleman KM, Smith CL. Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors. Front Biosci. 2001;6:D1379–91.CrossRefPubMed
29.
Kok M, Holm-Wigerup C, Hauptmann M, Michalides R, Stal O, Linn S, Landberg G. Estrogen receptor-alpha phosphorylation at serine-118 and tamoxifen response in breast cancer. J Natl Cancer Inst. 2009;101:1725–9.CrossRefPubMed
30.
Anbalagan M, Rowan BG. Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer. Mol Cell Endocrinol. 2015;418(Pt 3):264–72.CrossRefPubMed
31.
Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996;15:2174–83.PubMedPubMedCentral
32.
Chen D, Washbrook E, Sarwar N, Bates GJ, Pace PE, Thirunuvakkarasu V, Taylor J, Epstein RJ, Fuller-Pace FV, Egly JM, et al. Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. Oncogene. 2002;21:4921–31.CrossRefPubMed
33.
Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene. 2007;26:3203–13.CrossRefPubMed
34.
Cheng J, Zhang C, Shapiro DJ. A functional serine 118 phosphorylation site in estrogen receptor-alpha is required for down-regulation of gene expression by 17beta-estradiol and 4-hydroxytamoxifen. Endocrinology. 2007;148:4634–41.CrossRefPubMed
35.
Likhite VS, Stossi F, Kim K, Katzenellenbogen BS, Katzenellenbogen JA. Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid, and coregulators associated with alterations in estrogen and tamoxifen activity. Mol Endocrinol. 2006;20:3120–32.CrossRefPubMed
36.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–35.CrossRefPubMed
37.
Chen M, Cui YK, Huang WH, Man K, Zhang GJ. Phosphorylation of estrogen receptor alpha at serine 118 is correlated with breast cancer resistance to tamoxifen. Oncol Lett. 2013;6:118–24.PubMedPubMedCentral
38.
Yamashita H, Nishio M, Toyama T, Sugiura H, Kondo N, Kobayashi S, Fujii Y, Iwase H. Low phosphorylation of estrogen receptor alpha (ERalpha) serine 118 and high phosphorylation of ERalpha serine 167 improve survival in ER-positive breast cancer. Endocr Relat Cancer. 2008;15:755–63.CrossRefPubMed
39.
Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005;6:827–37.CrossRefPubMed
40.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90.CrossRefPubMed
41.
Herrero A, Pinto A, Colon-Bolea P, Casar B, Jones M, Agudo-Ibanez L, Vidal R, Tenbaum SP, Nuciforo P, Valdizan EM, et al. Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer Cell. 2015;28:170–82.CrossRefPubMed
42.
Bartholomeusz C, Gonzalez-Angulo AM, Liu P, Hayashi N, Lluch A, Ferrer-Lozano J, Hortobagyi GN. High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients. Oncologist. 2012;17:766–74.CrossRefPubMedPubMedCentral
43.
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263–84.CrossRefPubMed
44.
Li P, Xue WJ, Feng Y, Mao QS. Long non-coding RNA CASC2 suppresses the proliferation of gastric cancer cells by regulating the MAPK signaling pathway. Am J Transl Res. 2016;8:3522–9.PubMedPubMedCentral
45.
XS W, Wang XA, WG W, YP H, Li ML, Ding Q, Weng H, Shu YJ, Liu TY, Jiang L, et al. MALAT1 promotes the proliferation and metastasis of gallbladder cancer cells by activating the ERK/MAPK pathway. Cancer Biol Ther. 2014;15:806–14.CrossRef
46.
47.
Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993;75:487–93.CrossRefPubMed
48.
Giltnane JM, Balko JM. Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer. Discov Med. 2014;17:275–83.PubMed
49.
50.
Li G, Ci W, Karmakar S, Chen K, Dhar R, Fan Z, Guo Z, Zhang J, Ke Y, Wang L, et al. SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer. Cancer Cell. 2014;25:455–68.CrossRefPubMedPubMedCentral
51.
Carlos AR, Escandell JM, Kotsantis P, Suwaki N, Bouwman P, Badie S, Folio C, Benitez J, Gomez-Lopez G, Pisano DG, et al. ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets. Nat Commun. 2013;4:2697.CrossRefPubMed
Metadata
Title
Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer
Authors
Wan-xin Peng
Jian-guo Huang
Liu Yang
Ai-hua Gong
Yin-Yuan Mo
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0727-3

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