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Breast Cancer Research and Treatment

, Volume 127, Issue 2, pp 385–396 | Cite as

The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells

  • Paul T. R. Thiruchelvam
  • Chun-Fui Lai
  • Hui Hua
  • Ross S. Thomas
  • Antoni Hurtado
  • William Hudson
  • Andrew R. Bayly
  • Fiona J. Kyle
  • Manikandan Periyasamy
  • Andrew Photiou
  • Alan C. Spivey
  • Eric A. Ortlund
  • Richard J. Whitby
  • Jason S. Carroll
  • R. Charles Coombes
  • Laki Buluwela
  • Simak Ali
Preclinical study

Abstract

Estrogen receptor-α (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.

Keywords

Estrogen Estrogen receptor Gene regulation LRH-1 

Notes

Acknowledgments

We would like to thank D. McDonnell, D. D. Moore, J. J. Tremblay, R. S. Viger, C. Clyne, E. R. Simpson, and S. Wang for their liberal gifts of plasmids, and A. G. M. Barrett, M. Fuchter, and A. Jaxa-Chamiec for helpful discussions. We also thank A. M. Khan for help with bioinformatics analysis of the ER gene sequences. This study was supported by grants from Cancer Research UK, the Royal College of Surgeons, the Wellcome Trust, and the Department of Health-funded Imperial College Cancer Medicine Centre (ECMC) grant. We are also grateful for the support received from the NIHR Biomedical Research Centre funding scheme.

Conflict of interest statement

The authors declare no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Paul T. R. Thiruchelvam
    • 1
  • Chun-Fui Lai
    • 1
  • Hui Hua
    • 1
  • Ross S. Thomas
    • 1
  • Antoni Hurtado
    • 2
  • William Hudson
    • 3
  • Andrew R. Bayly
    • 4
  • Fiona J. Kyle
    • 1
  • Manikandan Periyasamy
    • 1
  • Andrew Photiou
    • 1
  • Alan C. Spivey
    • 4
  • Eric A. Ortlund
    • 3
  • Richard J. Whitby
    • 5
  • Jason S. Carroll
    • 2
  • R. Charles Coombes
    • 1
  • Laki Buluwela
    • 1
  • Simak Ali
    • 1
  1. 1.Department of OncologyImperial College London, Hammersmith HospitalLondonUK
  2. 2.Cancer Research UK, Cambridge Research Institute, Li Ka Shing CentreCambridgeUK
  3. 3.Department of BiochemistryEmory University School of MedicineAtlantaUSA
  4. 4.Department of ChemistryImperial College LondonLondonUK
  5. 5.School of ChemistryUniversity of SouthamptonHighfield, SouthamptonUK

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