Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids

Mol Cell Biol. 1997 Nov;17(11):6598-608. doi: 10.1128/mcb.17.11.6598.

Abstract

All-trans-retinoic acid (trans-RA) and other retinoids exert anticancer effects through two types of retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs). Previous studies demonstrated that the growth-inhibitory effects of trans-RA and related retinoids are impaired in certain estrogen-independent breast cancer cell lines due to their lower levels of RAR alpha and RARbeta. In this study, we evaluated several synthetic retinoids for their ability to induce growth inhibition and apoptosis in both trans-RA-sensitive and trans-RA-resistant breast cancer cell lines. Our results demonstrate that RXR-selective retinoids, particularly in combination with RAR-selective retinoids, could significantly induce RARbeta and inhibit the growth and induce the apoptosis of trans-RA-resistant, RAR alpha-deficient MDA-MB-231 cells but had low activity against trans-RA-sensitive ZR-75-1 cells that express high levels of RAR alpha. Using gel retardation and transient transfection assays, we found that the effects of RXR-selective retinoids on MDA-MB-231 cells were most likely mediated by RXR-nur77 heterodimers that bound to the RA response element in the RARbeta promoter and activated the RARbeta promoter in response to RXR-selective retinoids. In contrast, growth inhibition by RAR-selective retinoids in trans-RA-sensitive, RAR alpha-expressing cells most probably occurred through RXR-RAR alpha heterodimers that also bound to and activated the RARbeta promoter. In MDA-MB-231 clones stably expressing RAR alpha, both RARbeta induction and growth inhibition by RXR-selective retinoids were suppressed, while the effects of RAR-selective retinoids were enhanced. Together, our results demonstrate that activation of RXR can inhibit the growth of trans-RA-resistant MDA-MB-231 breast cancer cells and suggest that low cellular RAR alpha may regulate the signaling switch from RAR-mediated to RXR-mediated growth inhibition in breast cancer cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Binding, Competitive
  • Breast Neoplasms / metabolism*
  • Cell Division / drug effects
  • DNA-Binding Proteins / metabolism
  • Drug Resistance
  • Evaluation Studies as Topic
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Isomerism
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid / metabolism*
  • Receptors, Steroid
  • Retinoid X Receptors
  • Retinoids / pharmacology*
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism*
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Receptors, Steroid
  • Retinoid X Receptors
  • Retinoids
  • Transcription Factors
  • retinoic acid receptor beta
  • Tretinoin