Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1

J Biol Chem. 2009 Jan 2;284(1):345-353. doi: 10.1074/jbc.M804721200. Epub 2008 Oct 28.

Abstract

The synthetic rexinoid bexarotene (Targretin, LGD1069) inhibits the formation of both estrogen receptor-negative and estrogen receptor-positive breast cancer in preclinical models and controls the expression of growth-regulatory biomarkers, such as IGFBP-6 (insulin-like growth factor-binding protein 6), RARbeta, or cyclin D1. In this study, we identified a classical retinoic acid-responsive element in the first intron in the IGFBP-6 gene adjacent to a consensus AP-1 binding site, both elements essential for rexinoid-induced expression of IGFBP-6. In chromatin binding experiments, bexarotene increased the occupancy of the identified enhancer element by RXRalpha, RARbeta, cJun, cFos, and p300. In normal mammary epithelial cells and T47D breast cancer cells, small interfering RNA-mediated knockdown of all RXR isoforms or RARbeta, but not RARalpha or RARgamma alone, blocked the induction of IGFBP-6 by bexarotene. Simultaneous knockdown of RARalpha and RARgamma abrogated both the induction of RARbeta and the up-regulation and secretion of IGFBP-6. The suppression of either RARbeta or cJun by small interfering RNA blocked the recruitment of RXRalpha and cJun to the enhancer. These results demonstrate a novel cooperative interaction between retinoid receptors and AP-1 orchestrated by RARbeta and highlight a novel mechanism by which RARbeta can mediate the cancer-preventive effects of rexinoids.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Bexarotene
  • Cell Line, Tumor
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Gene Knockdown Techniques
  • Genes, fos / physiology
  • Humans
  • Insulin-Like Growth Factor Binding Protein 6 / biosynthesis*
  • Insulin-Like Growth Factor Binding Protein 6 / genetics
  • Introns / physiology
  • Mammary Glands, Human
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Response Elements / physiology*
  • Retinoic Acid Receptor alpha
  • Retinoic Acid Receptor gamma
  • Retinoid X Receptor alpha / genetics
  • Retinoid X Receptor alpha / metabolism
  • Tetrahydronaphthalenes / pharmacology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • Anticarcinogenic Agents
  • CCND1 protein, human
  • Insulin-Like Growth Factor Binding Protein 6
  • Proto-Oncogene Proteins c-jun
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha
  • Tetrahydronaphthalenes
  • Transcription Factor AP-1
  • retinoic acid receptor beta
  • Cyclin D1
  • Bexarotene
  • p300-CBP Transcription Factors