Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

The clock gene Per2 links the circadian system to the estrogen receptor

Oncogene volume 26, pages 7916–7920 (2007)Cite this article

Abstract

Circadian rhythms regulate diverse physiological processes including homeostatic functions of steroid hormones and their receptors. Estrogen receptor-α (ERα) is essential for normal mammary gland physiology and is a prognostic marker for the treatment of breast cancer. We report that Per2, a core clock gene, links the circadian cycle to the ERα signaling network. Binding of enhances ERα degradation, while suppression of Per2 levels leads to ERα stabilization. In turn, Per2 itself is estrogen inducible in these cells, suggesting a feedback mechanism to attenuate stimulation by estrogen. In addition, overexpression of Per2 in breast cancer cells leads to significant growth inhibition, loss of clonogenic ability and apoptosis. Taken together, these results further support a critical role for peripheral circadian regulation in tissue homeostasis and suggest a novel role for clock genes in estrogen receptor-positive breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG . (2005). Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26: 1241–1246.

    Article  CAS  Google Scholar 

  • Fu L, Pelicano H, Liu J, Huang P, Lee C . (2002). The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111: 41–50.

    Article  CAS  Google Scholar 

  • Gallego M, Virshup DM . (2007). Post-translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8: 139–148.

    Article  CAS  Google Scholar 

  • Hansen J . (2001). Light at night, shiftwork, and breast cancer risk. J Natl Cancer Inst 93: 1513–1515.

    Article  CAS  Google Scholar 

  • Hua H, Wang Y, Wan C, Liu Y, Zhu B, Yang C et al. (2006). Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Sci 97: 589–596.

    Article  CAS  Google Scholar 

  • Ishida N . (2007). Circadian clock, cancer and lipid metabolism. Neurosci Res 57: 483–490.

    Article  CAS  Google Scholar 

  • Ko CH, Takahashi JS . (2006). Molecular components of the mammalian circadian clock. Hum Mol Genet 20062: R271–R277.

    Article  Google Scholar 

  • Lowrey PL, Takahashi JS . (2004). Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet 5: 407–441.

    Article  CAS  Google Scholar 

  • Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H . (2003). Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255–259.

    Article  CAS  Google Scholar 

  • McDonnell DP, Norris JD . (2002). Connections and regulation of the human estrogen receptor. Science 296: 1642–1644.

    Article  CAS  Google Scholar 

  • Metz RP, Qu X, Laffin B, Earnest D, Porter WW . (2006). Circadian clock and cell cycle gene expression in mouse mammary epithelial cells and in the developing mouse mammary gland. Dev Dyn 235: 263–271.

    Article  CAS  Google Scholar 

  • Miller BH, McDearmon EL, Panda S, Hayes KR, Zhang J, Andrews JL et al. (2007). Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci USA 104: 3342–3347.

    Article  CAS  Google Scholar 

  • Nakamura TJ, Moriya T, Inoue S, Shimazoe T, Watanabe S, Ebihara S et al. (2005). Estrogen differentially regulates expression of Per1 and Per2 genes between central and peripheral clocks and between reproductive and nonreproductive tissues in female rats. J Neurosci Res 82: 622–630.

    Article  CAS  Google Scholar 

  • Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M et al. (2002). Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307–320.

    Article  CAS  Google Scholar 

  • Perrin JS, Segall LA, Harbour VL, Woodside B, Amir S . (2006). The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Proc Natl Acad Sci USA 103: 5591–5596.

    Article  CAS  Google Scholar 

  • Reid G, Denger S, Kos M, Gannon F . (2002). Human estrogen receptor-alpha: regulation by synthesis, modification and degradation. Cell Mol Life Sci 59: 821–831.

    Article  CAS  Google Scholar 

  • Reppert SM, Weaver DR . (2002). Coordination of circadian timing in mammals. Nature 418: 935–941.

    Article  CAS  Google Scholar 

  • Romagnolo D, Annab LA, Thompson TE, Risinger JI, Terry LA, Barrett JC et al. (1998). Estrogen upregulation of BRCA1 expression with no effect on localization. Mol Carcinog 22: 102–109.

    Article  CAS  Google Scholar 

  • Schibler U, Sassone-Corsi P . (2002). A web of circadian pacemakers. Cell 111: 919–922.

    Article  CAS  Google Scholar 

  • Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B et al. (2000). Interacting molecular loops in the mammalian circadian clock. Science 288: 1013–1019.

    Article  CAS  Google Scholar 

  • Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC et al. (2001). Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. Genes Dev 15: 1140–1151.

    Article  CAS  Google Scholar 

  • Sternlicht MD . (2006). Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res 8: 201.

    Article  Google Scholar 

  • Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH . (2002). Extensive and divergent circadian gene expression in liver and heart. Nature 417: 78–83.

    Article  CAS  Google Scholar 

  • Yager JD, Davidson NE . (2006). Estrogen carcinogenesis in breast cancer. N Engl J Med 354: 270–282.

    Article  CAS  Google Scholar 

  • Yagita K, Tamanini F, Yasuda M, Hoeijmakers JH, van der Horst GT, Okamura H . (2002). Nucleocytoplasmic shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock protein. EMBO J 21: 1301–1314.

    Article  CAS  Google Scholar 

  • Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M et al. (2006). Nuclear receptor expression links the circadian clock to metabolism. Cell 126: 801–810.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants, UCLA Cancer Gene Medicine Training grant and also in part by the Parker Hughes Trust, the Inger Foundation and the Mary Barry Foundation. H Phillip Koeffler is a member of the UCLA Jonsson Comprehensive Cancer Center and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, University of California, Los Angeles, CA, USA

    S Gery, R K Virk, K Chumakov, A Yu & H P Koeffler

Authors
  1. S Gery
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R K Virk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Chumakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H P Koeffler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Gery.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gery, S., Virk, R., Chumakov, K. et al. The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 26, 7916–7920 (2007). https://doi.org/10.1038/sj.onc.1210585

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210585

Keywords

This article is cited by

Search

Advanced search

Quick links