Dominant-negative nuclear receptor corepressor relieves transcriptional inhibition of retinoic acid receptor but does not alter the agonist/antagonist activities of the tamoxifen-bound estrogen receptor

Mol Endocrinol. 2003 Aug;17(8):1543-54. doi: 10.1210/me.2001-0144. Epub 2003 May 1.

Abstract

Repression of the transcriptional activities of the estrogen receptor (ER) is a main goal in the treatment of breast cancer. The antiestrogen tamoxifen is an effective therapy for breast cancer patients because it inhibits estrogen-stimulated gene expression and cell proliferation. Previous studies have implicated a complex containing the nuclear receptor corepressor (N-CoR) in the mechanism by which tamoxifen represses ER-mediated transcriptional activity. In the present study a truncated N-CoR construct was used to inhibit endogenous N-CoR activity in an ER-positive breast cancer cell line. This dominant-negative N-CoR was successful in relieving repression conferred by the unliganded retinoic acid receptor, but it failed to affect the transcriptional activity of the ER in the presence of tamoxifen. Correspondingly, the histone acetylation levels of nucleosomes on endogenous estrogen-responsive genes were unaltered in cells expressing the N-CoR dominant-negative, regardless of ligand. In addition, in vitro cell proliferation and in vivo tumor growth were unchanged in cells that express dominant-negative N-CoR. In conclusion, these results may reveal that N-CoR affects tamoxifen-liganded ER in a manner distinct from its influence on retinoic acid receptor-mediated transcriptional activity or that corepressors other than N-CoR may be involved in the ability of tamoxifen to repress estrogen-responsive transcription and tumor growth.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Division / drug effects
  • Cell Division / genetics
  • Estrogens / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Dominant
  • Humans
  • Mice
  • Mice, Nude
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Co-Repressor 1
  • Receptors, Estrogen / agonists
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / genetics*
  • Receptors, Retinoic Acid / genetics*
  • Receptors, Retinoic Acid / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Selective Estrogen Receptor Modulators / metabolism*
  • Selective Estrogen Receptor Modulators / pharmacology
  • Tamoxifen / metabolism*
  • Tamoxifen / pharmacology
  • Transcription, Genetic
  • Tumor Cells, Cultured

Substances

  • Estrogens
  • NCOR1 protein, human
  • Ncor1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Receptors, Estrogen
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Selective Estrogen Receptor Modulators
  • Tamoxifen