Skip to main content

Advertisement

SpringerLink
Log in

Aberrant methylation of miR-34b is associated with long-term shiftwork: a potential mechanism for increased breast cancer susceptibility

  • Original paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Purpose

Although the evidence linking exposure to light at night (LAN) and breast cancer risk continues to accumulate, the molecular mechanisms driving this association remain to be fully elucidated. We have previously suggested that long-term exposure to LAN through shiftwork may result in dysregulated patterns of methylation genome-wide. In this study, we investigate the link between miR-34b, a miRNA suggested to be an important tumor suppressor, and shiftwork-related breast cancer.

Methods

Methylation states in the miR-34b promoter region were previously compared between 10 female long-term shiftworkers and 10 folate intake- and age-matched female dayworkers participating in the Danish “Diet, Cancer and Health” prospective cohort study. In order to further explore the functional role of miR-34b in breast tumorigenesis, a genome-wide expression microarray was carried out in miR-34b-overexpressed MCF-7 breast cancer cells and the identified transcripts were further analyzed for network and functional interrelatedness using Ingenuity Pathway Analysis software.

Results

We observed a 49.1 % increase in miR-34b promoter methylation among shiftworkers at a CpG site in this region (p = 0.016). Transfection of the miR-34b mimic in an MCF-7 breast cancer cell line induced differential expression of 230 transcripts that are involved in the interferon-mediated antiviral response as well as apoptotic and antiproliferative gene networks.

Conclusions

Together, our results suggest that long-term shiftwork may increase the risk of breast cancer via methylation-based suppression of miR-34b and a consequent reduction in immunomediated anti-tumor capacity and support our previous findings that LAN may induce epigenetic alteration of cancer-relevant microRNAs.

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
Fig. 5

Similar content being viewed by others

References

  1. Akerstedt T (2003) Shift work and disturbed sleep/wakefulness. Occup Med (Lond) 53:89–94

    Article  Google Scholar 

  2. Knutsson A (2003) Health disorders of shift workers. Occup Med (Lond) 53:103–108

    Article  Google Scholar 

  3. Thomas C, Power C (2010) Shift work and risk factors for cardiovascular disease: a study at age 45 years in the 1958 British birth cohort. Eur J Epidemiol 25:305–314

    Article  PubMed  Google Scholar 

  4. van Mark A, Weiler SW, Schroder M et al (2010) The impact of shift work induced chronic circadian disruption on IL-6 and TNF-alpha immune responses. J Occup Med Toxicol 5:18

    Article  PubMed Central  PubMed  Google Scholar 

  5. Costa G, Haus E, Stevens R (2010) Shift work and cancer—considerations on rationale, mechanisms, and epidemiology. Scand J Work Environ Health 36:163–179

    Article  PubMed  Google Scholar 

  6. Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93:1557–1562

    Article  CAS  PubMed  Google Scholar 

  7. Hansen J (2006) Risk of breast cancer after night- and shift work: current evidence and ongoing studies in Denmark. Cancer Causes Control 17:531–537

    Article  PubMed  Google Scholar 

  8. Hansen J, Stevens RG (2012) Case–control study of shift-work and breast cancer risk in Danish nurses: impact of shift systems. Eur J Cancer 48:1722–1729

    Article  PubMed  Google Scholar 

  9. Reed VA (2011) Shift work, light at night, and the risk of breast cancer. AAOHN J. 59: 37–45; quiz 6

  10. Straif K, Baan R, Grosse Y et al (2007) Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol 8:1065–1066

    Article  PubMed  Google Scholar 

  11. Erren TC (2010) Shift work, cancer and “white-box” epidemiology: association and causation. Epidemiol Perspect Innov 7:11

    Article  PubMed Central  PubMed  Google Scholar 

  12. Shi F, Chen X, Fu A et al (2013) Aberrant DNA methylation of miR-219 promoter in long-term night shiftworkers. Environ Mol Mutagen 54:406–413

    Article  CAS  PubMed  Google Scholar 

  13. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  CAS  PubMed  Google Scholar 

  14. Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J (2008) Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res 68:2094–2105

    Article  CAS  PubMed  Google Scholar 

  15. Lopez-Serra P, Esteller M (2012) DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene 31:1609–1622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Lujambio A, Calin GA, Villanueva A et al (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA 105:13556–13561

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Pigazzi M, Manara E, Baron E, Basso G (2009) miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res 69:2471–2478

    Article  CAS  PubMed  Google Scholar 

  18. Leucci E, Cocco M, Onnis A et al (2008) MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation. J Pathol 216:440–450

    Article  CAS  PubMed  Google Scholar 

  19. He L, He X, Lim LP et al (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134

    Article  CAS  PubMed  Google Scholar 

  20. He X, He L, Hannon GJ (2007) The guardian’s little helper: microRNAs in the p53 tumor suppressor network. Cancer Res 67:11099–11101

    Article  CAS  PubMed  Google Scholar 

  21. Shi F, Chen X, Fu A et al (2013) Aberrant DNA methylation of miR-219 promoter in long-term night shiftworkers. Environ Mol Mutagen 54:406–413

    Article  CAS  PubMed  Google Scholar 

  22. Tjønneland A, Olsen A, Boll K et al (2007) Study design, exposure variables, and socioeconomic determinants of participation in diet, cancer and health: a population-based prospective cohort study of 57,053 men and women in Denmark. Scand J Public Health 35:432–441

    Article  PubMed  Google Scholar 

  23. Zhu Y, Stevens RG, Hoffman AE et al (2011) Epigenetic impact of long-term shiftwork: pilot evidence from circadian genes and whole-genome methylation analysis. Chronobiol Int 28:852–861

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Jacobs DI, Hansen J, Fu A et al (2013) Methylation alterations at imprinted genes detected among long-term shiftworkers. Environ Mol Mutagen 54:141–146

    Article  CAS  PubMed  Google Scholar 

  25. Chudin E, Kruglyak S, Baker SC, Oeser S, Barker D, McDaniel TK (2006) A model of technical variation of microarray signals. J Comput Biol 13:996–1003

    Article  CAS  PubMed  Google Scholar 

  26. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  27. Calvano SE, Xiao W, Richards DR et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037

    Article  CAS  PubMed  Google Scholar 

  28. Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386

    Article  CAS  PubMed  Google Scholar 

  29. Kirchhoff S, Schaper F, Hauser H (1993) Interferon regulatory factor 1 (IRF-1) mediates cell growth inhibition by transactivation of downstream target genes. Nucleic Acids Res 21:2881–2889

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Ernst J, Kellis M (2010) Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol 28:817–825

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Hermeking H (2007) p53 enters the microRNA world. Cancer Cell 12:414–418

    Article  CAS  PubMed  Google Scholar 

  32. Bommer GT, Gerin I, Feng Y et al (2007) p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 17:1298–1307

    Article  CAS  PubMed  Google Scholar 

  33. He L, He X, Lim LP et al (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134

    Article  CAS  PubMed  Google Scholar 

  34. Raver-Shapira N, Marciano E, Meiri E et al (2007) Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 26:731–743

    Article  CAS  PubMed  Google Scholar 

  35. Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY (2007) MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res 67:8433–8438

    Article  CAS  PubMed  Google Scholar 

  36. He L, He X, Lowe SW, Hannon GJ (2007) microRNAs join the p53 network–another piece in the tumour-suppression puzzle. Nat Rev Cancer 7:819–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Boominathan L (2010) The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. Cancer Metastasis Rev 29:613–639

    Article  CAS  PubMed  Google Scholar 

  38. Takaoka A, Hayakawa S, Yanai H et al (2003) Integration of interferon-[alpha]/[beta] signalling to p53 responses in tumour suppression and antiviral defence. Nature 424:516–523

    Article  CAS  PubMed  Google Scholar 

  39. Ossina NK, Cannas A, Powers VC et al (1997) Interferon-γ modulates a p53-independent apoptotic pathway and apoptosis-related gene expression. J Biol Chem 272:16351–16357

    Article  CAS  PubMed  Google Scholar 

  40. Chen X, Hu H, Guan X et al (2012) CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. Int J Cancer 130:1607–1613

    Article  CAS  PubMed  Google Scholar 

  41. Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199

    Article  CAS  PubMed  Google Scholar 

  42. Kalimutho M, Di Cecilia S, Del Vecchio Blanco G et al (2011) Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer. Br J Cancer 104:1770–1778

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Pigazzi M, Manara E, Baron E, Basso G (2009) miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res 69:2471–2478

    Article  CAS  PubMed  Google Scholar 

  44. Toyota M, Suzuki H, Sasaki Y et al (2008) Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res 68:4123–4132

    Article  CAS  PubMed  Google Scholar 

  45. Wang Z, Chen Z, Gao Y et al (2011) DNA hypermethylation of microRNA-34b/c has prognostic value for stage non-small cell lung cancer. Cancer Biol Ther 11:490–496

    Article  CAS  PubMed  Google Scholar 

  46. Wiggins JF, Ruffino L, Kelnar K et al (2010) Development of a lung cancer therapeutic based on the tumor suppressor microrna-34. Cancer Res 70:5923–5930

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Kasinski AL, Slack FJ (2012) miRNA-34 prevents cancer initiation and progression in a therapeutically resistant k-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res 72:5576–5587

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Widschwendter M, Apostolidou S, Raum E et al (2008) Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS ONE 3:e2656

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institutes of Health Grants (ES018915 and CA62006). Ran Liu’s visit at Yale University was supported by the China Scholarship Council (CSC). The Diet, Cancer and Health cohort was funded by the Danish Cancer Society.

Conflict of interest

The authors declare no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA

    Ran Liu, Daniel I. Jacobs, Alan Fu & Yong Zhu

  2. Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China

    Ran Liu

  3. Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark

    Johnni Hansen

  4. University of Connecticut Health Center, Farmington, 06030-6325, CT, USA

    Richard G. Stevens

Authors
  1. Ran Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel I. Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johnni Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alan Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard G. Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Zhu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 33 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, R., Jacobs, D.I., Hansen, J. et al. Aberrant methylation of miR-34b is associated with long-term shiftwork: a potential mechanism for increased breast cancer susceptibility. Cancer Causes Control 26, 171–178 (2015). https://doi.org/10.1007/s10552-014-0494-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-014-0494-z

Keywords

Search

Navigation