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The Re-Expression of Estrogen Receptor in Estrogen Receptor-Negative Breast Cancer and Restoration of Anti-Estrogen Responses

  • Jill Bayliss
  • Amy Hilger
  • Prakash Vishnu
  • Kathleen Diehl
  • Dorraya El-Ashry

Abstract

Loss of estrogen receptor α ERα in breast cancer correlates with a more aggressive, tamoxifen resistant phenotype. ERα-negative tumors often display overexpression or amplification of growth factor receptors of the erbB family, particularly EGFR and erbB-2, and consequently, elevated growth factor signaling and resultant MAP kinase (ERK) activity. We have previously shown that overexpression/hyperactivation of EGFR or erbB-2, or the downstream effectors Raf or MEK, in ERα+, estrogen-dependent MCF-7 cells results in the acquisition of estrogen-independence and loss of ERα expression. We have shown that the common downstream effector of ERα downregulation in all our model cell lines is hyperactive MAPK and that inhibition of this hyperactive MAPK restores ERα expression. Microarray expression profiling of these hyperactive MAPK model cell lines revealed a hyperactive MAPK signature that correlates with ERα-breast cancer and not ERα+ breast cancer. We have more recently extended these observations to established ERα-breast cancer cell lines and primary cultures from ERα-breast tumor specimens. Inhibition of MAPK in these ERα-breast cancer cells restores ERα expression and associated with this re-expression of ERα is the acquisition of anti-estrogen responses. These data demonstrate the dynamic nature of ERα expression in breast cancer cells and the ability to impact ERα expression by altering cellular signaling pathways. Further, they suggest a potential novel therapeutic strategy for ERα-breast cancer: inhibition of MAPK activity to restore both ERα expression and anti-estrogen responses.

Keywords

Estrogen receptor loss MAPK Microarray profiling 

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Jill Bayliss
  • Amy Hilger
  • Prakash Vishnu
  • Kathleen Diehl
  • Dorraya El-Ashry
    • 1
  1. 1.Department of Internal Medicine Division of Hematology/OncologyUniversity of Miami Miller School of MedicineMiamiUSA

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