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Breast Cancer Research and Treatment

, Volume 134, Issue 2, pp 569–581 | Cite as

Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter

  • V. Bartella
  • P. Rizza
  • I. Barone
  • D. Zito
  • F. Giordano
  • C. Giordano
  • S. Catalano
  • L. Mauro
  • D. Sisci
  • M. L. Panno
  • S. A. W. Fuqua
  • S. Andò
Preclinical study

Abstract

Human estrogen receptors alpha and beta are crucially involved in the regulation of mammary growth and development. Normal breast tissues display a relative higher expression of ER beta than ER alpha, which drastically changes during breast tumorogenesis. Thus, it is reasonable to suggest that a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanisms underlying the potential opposing roles played by the two estrogen receptors on tumor cell growth remain to be elucidated. In the present study, we have demonstrated that ER beta overexpression in breast cancer cells decreases cell proliferation and down-regulates ER alpha mRNA and protein content, along with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ER alpha promoter region, showed that elevated levels of ER beta down-regulated basal ER alpha promoter activity. Furthermore, site-directed mutagenesis and deletion analysis revealed that the proximal GC-rich motifs at −223 and −214 are critical for the ER beta-induced ER alpha down-regulation in breast cancer cells. This occurred through ER beta-Sp1 protein–protein interactions within the ER alpha promoter region and the recruitment of a corepressor complex containing the nuclear receptor corepressor NCoR, accompanied by hypoacetylation of histone H4 and displacement of RNA-polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effects of ER beta on ER alpha gene expression and cell proliferation. Our results provide evidence for a novel mechanism by which overexpression of ER beta through NCoR is able to down regulate ER alpha gene expression, thus blocking ER alpha’s driving role on breast cancer cell growth.

Keywords

Breast cancer Estrogen receptor alpha Estrogen receptor beta NCoR corepressor 

Notes

Acknowledgments

This study was supported by PRIN 2009 and AIRC grants 2011. Reintegration AIRC/Marie Curie International Fellowship in Cancer Research to IB. NIH/NCI R01 CA72038 to SAWF.

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • V. Bartella
    • 1
  • P. Rizza
    • 2
  • I. Barone
    • 2
    • 3
  • D. Zito
    • 1
  • F. Giordano
    • 2
  • C. Giordano
    • 3
  • S. Catalano
    • 1
    • 3
  • L. Mauro
    • 2
  • D. Sisci
    • 1
    • 3
  • M. L. Panno
    • 2
  • S. A. W. Fuqua
    • 4
  • S. Andò
    • 2
    • 3
  1. 1.Department of Pharmaco-BiologyUniversity of CalabriaArcavacata di RendeItaly
  2. 2.Department of Cellular Biology, Faculty of Pharmacy, Nutritional and Health SciencesUniversity of CalabriaArcavacata di RendeItaly
  3. 3.Centro SanitarioUniversity of CalabriaArcavacata di RendeItaly
  4. 4.Lester and Sue Smith Breast Center and Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA

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