Skip to main content

Advertisement

SpringerLink
Log in

Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Expression of HOX transcript antisense intergenic RNA (HOTAIR)—a long non-coding RNA—has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that HOTAIR expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers (P = 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples (P = 0.0086, HR 1.985). In ER-negative tumor samples, we are not able to detect a prognostic value of HOTAIR expression, probably due to the limited sample size. These results are successfully validated in an independent dataset with similar associations (P = 0.018, HR 1.825). In conclusion, our findings suggest that HOTAIR expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, Dunham I, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kelllis M, Khatun J, Kheradpour P, Kundaje A, Lassmann T, Li Q, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SC, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HS, Yip KY, Zhuang J, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M, Pazin MJ, Lowdon RF, Dillon LA, Adams LB, Kelly CJ, Zhang J, Wexler JR, Green ED, Good PJ, Feingold EA, Bernstein BE, Birney E, Crawford GE, Dekker J, Elinitski L, Farnham PJ, Gerstein M, Giddings MC, Gingeras TR, Green ED, Guigo R, Hardison RC, Hubbard TJ, Kellis M, Kent WJ, Lieb JD, Margulies EH, Myers RM, Snyder M, Starnatoyannopoulos JA, Tennebaum SA, Weng Z, White KP, Wold B, Khatun J, Yu Y, Wrobel J, Risk BA, Gunawardena HP, Kuiper HC, Maier CW, Xie L, Chen X, Giddings MC, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Kheradpour P, Mikkelsen TS, Gillespie S, Goren A, Ram O, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Ward LD, Altshuler RC, Eaton ML, Kellis M, Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Batut P, Bell I, Bell K, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena HP, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Li G, Luo OJ, Park E, Preall JB, Presaud K, Ribeca P, Risk BA, Robyr D, Ruan X, Sammeth M, Sandu KS, Schaeffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Hayashizaki Y, Harrow J, Gerstein M, Hubbard TJ, Reymond A, Antonarakis SE, Hannon GJ, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR, Rosenbloom KR, Sloan CA, Learned K, Malladi VS, Wong MC, Barber GP, Cline MS, Dreszer TR, Heitner SG, Karolchik D, Kent WJ, Kirkup VM, Meyer LR, Long JC, Maddren M, Raney BJ, Furey TS, Song L, Grasfeder LL, Giresi PG, Lee BK, Battenhouse A, Sheffield NC, Simon JM, Showers KA, Safi A, London D, Bhinge AA, Shestak C, Schaner MR, Kim SK, Zhang ZZ, Mieczkowski PA, Mieczkowska JO, Liu Z, McDaniell RM, Ni Y (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74. doi:10.1038/nature11247

    Article  PubMed  CAS  Google Scholar 

  2. Bertone P, Stolc V, Royce TE, Rozowsky JS, Urban AE, Zhu X, Rinn JL, Tongprasit W, Samanta M, Weissman S, Gerstein M, Snyder M (2004) Global identification of human transcribed sequences with genome tiling arrays. Science 306:2242–2246. doi:10.1126/science.1103388

    Article  PubMed  CAS  Google Scholar 

  3. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789. doi:10.1101/gr.132159.111

    Article  PubMed  CAS  Google Scholar 

  4. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25:1915–1927. doi:10.1101/gad.17446611

    Article  PubMed  CAS  Google Scholar 

  5. Wapinski O, Chang HY (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21:354–361. doi:10.1016/j.tcb.2011.04.001

    Article  PubMed  CAS  Google Scholar 

  6. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227. doi:10.1038/nature07672

    Article  PubMed  CAS  Google Scholar 

  7. Huarte M, Rinn JL (2010) Large non-coding RNAs: missing links in cancer? Hum Mol Genet 19:R152–R161. doi:10.1093/hmg/ddq353

    Article  PubMed  CAS  Google Scholar 

  8. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea MD, Thomas K, Presser A, Bernstein BE, van OA, Regev A, Lander ES, Rinn JL (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA 106:11667–11672. doi:10.1073/pnas.0904715106

    Article  PubMed  CAS  Google Scholar 

  9. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129:1311–1323. doi:10.1016/j.cell.2007.05.022

    Article  PubMed  CAS  Google Scholar 

  10. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464:1071–1076. doi:10.1038/nature08975

    Article  PubMed  CAS  Google Scholar 

  11. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, Tanaka F, Shibata K, Suzuki A, Komune S, Miyano S, Mori M (2011) Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res 71:6320–6326. doi:10.1158/0008-5472.CAN-11-1021

    Article  PubMed  CAS  Google Scholar 

  12. Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, Zheng SS (2011) Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol 18:1243–1250. doi:10.1245/s10434-011-1581-y

    Article  PubMed  Google Scholar 

  13. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S (2013) HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 32:1616–1625. doi:10.1038/onc.2012.193

    Article  PubMed  CAS  Google Scholar 

  14. Geng YJ, Xie SL, Li Q, Ma J, Wang GY (2011) Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res 39:2119–2128

    Article  PubMed  CAS  Google Scholar 

  15. Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H, Takamaru H, Yamamoto E, Maruyama R, Nobuoka T, Miyazaki Y, Nishida T, Bamba T, Kanda T, Ajioka Y, Taguchi T, Okahara S, Takahashi H, Nishida Y, Hosokawa M, Hasegawa T, Tokino T, Hirata K, Imai K, Toyota M, Shinomura Y (2012) Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Res 72:1126–1136. doi:10.1158/0008-5472.CAN-11-1803

    Article  PubMed  CAS  Google Scholar 

  16. Endo H, Shiroki T, Nakagawa T, Yokoyama M, Tamai K, Yamanami H, Fujiya T, Sato I, Yamaguchi K, Tanaka N, Iijima K, Shimosegawa T, Sugamura K, Satoh K (2013) Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer. PLoS One 8:e77070. doi:10.1371/journal.pone.0077070

    Article  PubMed  CAS  Google Scholar 

  17. Ritchie ME, Silver J, Oshlack A, Holmes M, Diyagama D, Holloway A, Smyth GK (2007) A comparison of background correction methods for two-colour microarrays. Bioinformatics 23:2700–2707. doi:10.1093/bioinformatics/btm412

    Article  PubMed  CAS  Google Scholar 

  18. Grambsch PM, Therneau TM (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81:515–526. doi:10.2307/2337123

    Article  Google Scholar 

  19. Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J (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  PubMed  CAS  Google Scholar 

  20. Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, Liu ET, Miller L, Nordgren H, Ploner A, Sandelin K, Shaw PM, Smeds J, Skoog L, Wedren S, Bergh J (2005) Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res 7:R953–R964

    Article  PubMed  CAS  Google Scholar 

  21. Chen C, Grennan K, Badner J, Zhang D, Gershon E, Jin L, Liu C (2011) Removing batch effects in analysis of expression microarray data: an evaluation of six batch adjustment methods. PLoS One 6:e17238. doi:10.1371/journal.pone.0017238

    Article  PubMed  CAS  Google Scholar 

  22. Chisholm KM, Wan Y, Li R, Montgomery KD, Chang HY, West RB (2012) Detection of long non-coding RNA in archival tissue: correlation with polycomb protein expression in primary and metastatic breast carcinoma. PLoS One 7:e47998. doi:10.1371/journal.pone.0047998

    Article  PubMed  CAS  Google Scholar 

  23. Lu L, Zhu G, Zhang C, Deng Q, Katsaros D, Mayne ST, Risch HA, Mu L, Canuto EM, Gregori G, Benedetto C, Yu H (2012) Association of large noncoding RNA HOTAIR expression and its downstream intergenic CpG island methylation with survival in breast cancer. Breast Cancer Res Treat 136:875–883. doi:10.1007/s10549-012-2314-z

    Article  PubMed  CAS  Google Scholar 

  24. Perou CM, Sorlie T, Eisen MB, van de RM, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  PubMed  CAS  Google Scholar 

  25. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de RM, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein LP, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  PubMed  CAS  Google Scholar 

  26. Reis-Filho JS, Pusztai L (2011) Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet 378:1812–1823. doi:10.1016/S0140-6736(11)61539-0

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by the Danish Council for Independent Research (FSS), the Danish Ministry of Interior, University of Southern Denmark, The Danish Council for Strategic Research (DBCG-TIBCAT) Dansk Kræftforsknings Fond, Breast Friends, Fonden til Lægevidenskabens Fremme, Københavns Universitets Fond for Kræftforskning, Arkitekt H. Hjortenberg & hustrus D. Hjortenbergs Fond, Carl J. Beckers Fond, Grosserer A.V. Lykfeldts Legat, Tømrermester Jørgen Holm & hustru Elisa F. Hansens Midelegat and Meta & Håkon Baggers Fond. The authors thank Charlotte Skouboe Landré for technical assistance with RNA purification.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics statement

The study was approved by the Danish Ethical Committee System (S-VF-20020142). The study was retrospective and we did not obtain informed consent from the patients involved in the study as approved by the Ethical Committee.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Kristina P. Sørensen, Mads Thomassen, Qihua Tan, Mark Burton, Martin J. Larsen & Torben A. Kruse

  2. Human Genetics, Clinical Institute, University of Southern Denmark, Odense, Denmark

    Kristina P. Sørensen, Mads Thomassen, Mark Burton, Martin J. Larsen & Torben A. Kruse

  3. Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark

    Qihua Tan

  4. Department of Pathology, Odense University Hospital, Odense, Denmark

    Martin Bak

  5. Department of Oncology, Odense University Hospital, Odense, Denmark

    Søren Cold

Authors
  1. Kristina P. Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mads Thomassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qihua Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Bak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Søren Cold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Burton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin J. Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Torben A. Kruse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristina P. Sørensen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 344 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sørensen, K.P., Thomassen, M., Tan, Q. et al. Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat 142, 529–536 (2013). https://doi.org/10.1007/s10549-013-2776-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-013-2776-7

Keywords

Search

Navigation