ABSTRACT Metastasis in breast cancer carries a disproportionately worse prognosis than localized primary disease. To identify microRNAs (miRNA) involved in metastasis, the expression of 254

miRNAs was measured across the following cell lines using microarray analysis: MDA-MB-231 breast cancer cells, cells that grew as a tumor in the mammary fat pad of nude mice (TMD-231),

metastatic disease to the lungs (LMD-231), bone (BMD-231) and adrenal gland (ADMD-231). A brain-seeking variant of this cell line (231-BR) was used additionally in validation studies. Twenty

miRNAs were upregulated and seven were downregulated in metastatic cancer cells compared with TMD-231 cells. The expression of the tumor suppressor miRNAs let-7 and miR-22 was consistently

reading frame C17orf91, and the promoter/enhancer of C17orf91 drives miR-22 expression. We observed elevated C17orf91 expression in non-basal subtype compared with basal subtype breast

cancers. In contrast, elevated expression of EVI-1 was observed in basal subtype and was associated with poor outcome in estrogen receptor-negative breast cancer patients. These results

suggest that metastatic cancer cells increase specific oncogenic signaling proteins through downregulation of miRNAs. Identifying such metastasis-specific oncogenic pathways may help to

manipulate tumor behavior and aid in the design of more effective targeted therapies. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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AND _MIR-99A-3P_ REGULATION ON ONCOGENIC GENES Article 12 November 2020 TRIPLE NEGATIVE AGGRESSIVE PHENOTYPE CONTROLLED BY MIR-135B AND MIR-365: NEW THERANOSTICS CANDIDATES Article Open

access 22 March 2021 ROLES OF MIR-20A-5P IN BREAST CANCER BASED ON THE CLINICAL AND MULTI-OMIC (CAMO) COHORT AND IN VITRO STUDIES Article Open access 23 October 2024 ACCESSION CODES

ACCESSIONS GENE EXPRESSION OMNIBUS * GSE11121 REFERENCES * Bhat-Nakshatri P, Campbell RA, Patel NM, Newton TR, King AJ, Marshall MS _et al_. (2004). Tumour necrosis factor and PI3-kinase

control oestrogen receptor alpha protein level and its transrepression function. _Br J Cancer_ 90: 853–859. Article  CAS  Google Scholar  * Bhat-Nakshatri P, Wang G, Collins NR, Thomson MJ,

Geistlinger TR, Carroll JS _et al_. (2009). Estradiol-regulated microRNAs control estradiol response in breast cancer cells. _Nucleic Acids Res_ 37: 4850–4861. Article  CAS  Google Scholar 

* Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ _et al_. (2007). MicroRNA expression profiling of human breast cancer identifies new markers of tumour subtype. _Genome

Biol_ 8: R214. Article  Google Scholar  * Campbell MR, Amin D, Moasser MM . (2010). HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer

therapy. _Clin Cancer Res_ 16: 1373–1383. Article  CAS  Google Scholar  * Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P _et al_. (2009). The estrogen

receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. _Proc Natl Acad Sci USA_ 106: 15732–15737. Article  CAS  Google Scholar  * Chang TC, Yu D, Lee

YS, Wentzel EA, Arking DE, West KM _et al_. (2008). Widespread microRNA repression by Myc contributes to tumorigenesis. _Nat Genet_ 40: 43–50. Article  CAS  Google Scholar  * Chua HL,

Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H . (2007). NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial

cells: potential involvement of ZEB-1 and ZEB-2. _Oncogene_ 26: 711–724. Article  CAS  Google Scholar  * Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B _et al_. (2007).

Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. _Clin Cancer Res_ 13:

3207–3214. Article  CAS  Google Scholar  * Dykxhoorn DM, Wu Y, Xie H, Yu F, Lal A, Petrocca F _et al_. (2009). miR-200 enhances mouse breast cancer cell colonization to form distant

metastases. _PLoS One_ 4: e7181. Article  Google Scholar  * Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM . (2006). Concordant regulation of gene expression by

hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. _J Biol Chem_ 281: 15215–15226. Article  CAS  Google Scholar  * Friedl P,

Wolf K . (2003). Tumour-cell invasion and migration: diversity and escape mechanisms. _Nat Rev Cancer_ 3: 362–374. Article  CAS  Google Scholar  * Gibbons DL, Lin W, Creighton CJ, Rizvi ZH,

Gregory PA, Goodall GJ _et al_. (2009). Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. _Genes Dev_ 23: 2140–2151. Article  CAS

  Google Scholar  * Goyama S, Nitta E, Yoshino T, Kako S, Watanabe-Okochi N, Shimabe M _et al_. (2010). EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional

repression and bone marrow immortalization. _Leukemia_ 24: 81–88. Article  CAS  Google Scholar  * Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L _et al_. (2008).

Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. _J Natl Cancer Inst_ 100: 1092–1103. Article  CAS  Google Scholar  * Gupta GP, Minn AJ, Kang Y, Siegel

PM, Serganova I, Cordon-Cardo C _et al_. (2005). Identifying site-specific metastasis genes and functions. _Cold Spring Harb Symp Quant Biol_ 70: 149–158. Article  CAS  Google Scholar  *

Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q _et al_. (2010). An online survival analysis tool to rapidly assess the effect of 22 277 genes on breast cancer prognosis using

microarray data of 1809 patients. _Breast Cancer Res Treat_ 123: 725–731. Article  Google Scholar  * Helbig G, Christopherson II KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD _et

al_. (2003). NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. _J Biol Chem_ 278: 21631–21638. Article  CAS  Google

Scholar  * Hoser M, Baader SL, Bosl MR, Ihmer A, Wegner M, Sock E . (2007). Prolonged glial expression of Sox4 in the CNS leads to architectural cerebellar defects and ataxia. _J Neurosci_

27: 5495–5505. Article  CAS  Google Scholar  * Hurst DR, Edmonds MD, Welch DR . (2009). Metastamir: the field of metastasis-regulatory microRNA is spreading. _Cancer Res_ 69: 7495–7498.

Article  CAS  Google Scholar  * Ibarra I, Erlich Y, Muthuswamy SK, Sachidanandam R, Hannon GJ . (2007). A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells.

_Genes Dev_ 21: 3238–3243. Article  CAS  Google Scholar  * Iliopoulos D, Malizos KN, Oikonomou P, Tsezou A . (2008). Integrative microRNA and proteomic approaches identify novel

osteoarthritis genes and their collaborative metabolic and inflammatory networks. _PLoS One_ 3: e3740. Article  Google Scholar  * Inui M, Martello G, Piccolo S . (2010). MicroRNA control of

signal transduction. _Nat Rev Mol Cell Biol_ 11: 252–263. Article  CAS  Google Scholar  * Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C _et al_. (2003). A multigenic

program mediating breast cancer metastasis to bone. _Cancer Cell_ 3: 537–549. Article  CAS  Google Scholar  * Koshiol J, Wang E, Zhao Y, Marincola F, Landi MT . (2010). Strengths and

limitations of laboratory procedures for microRNA detection. _Cancer Epidemiol Biomarkers Prev_ 19: 907–911. Article  CAS  Google Scholar  * Kumano K, Kurokawa M . (2010). The role of

Runx1/AML1 and Evi-1 in the regulation of hematopoietic stem cells. _J Cell Physiol_ 222: 282–285. Article  CAS  Google Scholar  * Lewis BP, Burge CB, Bartel DP . (2005). Conserved seed

pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. _Cell_ 120: 15–20. Article  CAS  Google Scholar  * Liu Y, Chen L, Ko TC, Fields AP,

Thompson EA . (2006). Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT. _Oncogene_ 25: 3565–3575. Article  CAS  Google Scholar 

* Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, Benes V _et al_. (2009). Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. _Cancer

Res_ 69: 8332–8340. Article  CAS  Google Scholar  * Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK _et al_. (2006). Optimized high-throughput microRNA expression profiling

provides novel biomarker assessment of clinical prostate and breast cancer biopsies. _Mol Cancer_ 5: 24. Article  Google Scholar  * Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A

_et al_. (2005). An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. _Proc Natl Acad Sci USA_ 102:

13550–13555. Article  CAS  Google Scholar  * Nagaraja AK, Creighton CJ, Yu Z, Zhu H, Gunaratne PH, Reid JG _et al_. (2010). A link between mir-100 and FRAP1/mTOR in clear cell ovarian

cancer. _Mol Endocrinol_ 24: 447–463. Article  CAS  Google Scholar  * Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA . (2009). MicroRNAs—the micro steering wheel of tumour metastases.

_Nat Rev Cancer_ 9: 293–302. Article  CAS  Google Scholar  * O'Day E, Lal A . (2010). MicroRNAs and their target gene networks in breast cancer. _Breast Cancer Res_ 12: 201. Article 

Google Scholar  * Pandey DP, Picard D . (2009). miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. _Mol Cell Biol_ 29: 3783–3790. Article  CAS  Google

Scholar  * Ramaswamy S, Ross KN, Lander ES, Golub TR . (2003). A molecular signature of metastasis in primary solid tumors. _Nat Genet_ 33: 49–54. Article  CAS  Google Scholar  * Richardson

AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A _et al_. (2006). X chromosomal abnormalities in basal-like human breast cancer. _Cancer Cell_ 9: 121–132. Article  CAS  Google Scholar  *

Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H _et al_. (2008). The humoral immune system has a key prognostic impact in node-negative breast cancer. _Cancer Res_ 68: 5405–5413.

Article  CAS  Google Scholar  * Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM _et al_. (2007). Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive

HER3. _Nature_ 445: 437–441. Article  CAS  Google Scholar  * Shimabe M, Goyama S, Watanabe-Okochi N, Yoshimi A, Ichikawa M, Imai Y _et al_. (2009). Pbx1 is a downstream target of Evi-1 in

hematopoietic stem/progenitors and leukemic cells. _Oncogene_ 28: 4364–4374. Article  CAS  Google Scholar  * Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J _et al_. (2006). Gene

expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. _J Natl Cancer Inst_ 98: 262–272. Article  CAS  Google Scholar  * Steeg PS

. (2006). Tumor metastasis: mechanistic insights and clinical challenges. _Nat Med_ 12: 895–904. Article  CAS  Google Scholar  * Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R .

(2008). Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. _Mol Cancer Ther_ 7: 464–473. Article  CAS  Google Scholar  * Tavazoie SF,

Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD _et al_. (2008). Endogenous human microRNAs that suppress breast cancer metastasis. _Nature_ 451: 147–152. Article  CAS  Google Scholar  *

Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC _et al_. (2009). A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. _Cell_ 137: 1032–1046.

Article  CAS  Google Scholar  * Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B _et al_. (2008). Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase

EZH2 in cancer. _Science_ 322: 1695–1699. Article  CAS  Google Scholar  * Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F _et al_. (2005). Gene-expression profiles to predict

distant metastasis of lymph-node-negative primary breast cancer. _Lancet_ 365: 671–679. Article  CAS  Google Scholar  * Wieser R . (2007). The oncogene and developmental regulator EVI1:

expression, biochemical properties, and biological functions. _Gene_ 396: 346–357. Article  CAS  Google Scholar  * Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S

_et al_. (2007). Induced pluripotent stem cell lines derived from human somatic cells. _Science_ 318: 1917–1920. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This work

is supported by Indiana University Simon Cancer Center Pilot grant and by Komen for Cure grant BCTR0601111 to HN. JBP and RMB are supported by National Institutes of Health Training Grants

T32 DK07519 and T32 CA111198, respectively. HN is Marian J Morrison Professor of Breast Cancer Research. AUTHOR INFORMATION Author notes * J B Patel and H N Appaiah: These authors

contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA J B Patel, H N Appaiah, R M Burnett, P

Bhat-Nakshatri & H Nakshatri * Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA G Wang & Y Liu * Department of Pathology, Indiana University

School of Medicine, Indianapolis, IN, USA R Mehta & S Badve * Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical School, Nashville, TN, USA M J

Thomson * Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA S Hammond * Laboratory of Molecular

Pharmacology, Center for Cancer Research National Cancer Institute, Bethesda, MD, USA P Steeg * Department of Biochemistry and Molecular Biology, Indiana University School of Medicine,

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declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Patel, J., Appaiah, H., Burnett, R. _et al._ Control of EVI-1 oncogene

expression in metastatic breast cancer cells through microRNA miR-22. _Oncogene_ 30, 1290–1301 (2011). https://doi.org/10.1038/onc.2010.510 Download citation * Received: 06 May 2010 *

Revised: 30 September 2010 * Accepted: 30 September 2010 * Published: 08 November 2010 * Issue Date: 17 March 2011 * DOI: https://doi.org/10.1038/onc.2010.510 SHARE THIS ARTICLE Anyone you

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Springer Nature SharedIt content-sharing initiative KEYWORDS * breast cancer * metastasis * microRNA * miR-22 * let-7