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Fulvestrant up regulates UGT1A4 and MRPs through ERα and c-Myb pathways: a possible primary drug disposition

Vineetha K Edavana1, Rosalind B Penney, Aiwei Yao-Borengasser

  • 1Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, #580, Little Rock, AR 72205 USA.

Springerplus
|December 4, 2013
PubMed

Insights

Fulvestrant increases UDP glucuronosyltransferase 1A4 (UGT1A4) and multidrug resistance-associated proteins (MRPs), impacting drug metabolism and resistance in breast cancer treatment.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Fulvestrant is an antiestrogen used for ER-positive breast cancer resistant to tamoxifen.
  • Previous studies did not assess fulvestrant's impact on phase II metabolism or drug resistance.
  • The role of UGT1A4 and MRPs in fulvestrant's efficacy requires further investigation.

Purpose of the Study:

  • To investigate fulvestrant's effects on UDP glucuronosyltransferase 1A4 (UGT1A4) and multidrug resistance-associated proteins (MRPs) expression.
  • To explore the mechanisms underlying fulvestrant-induced UGT1A4 upregulation.
  • To assess the clinical significance of UGT1A4 and MRPs in fulvestrant therapy.

Main Methods:

  • Cell culture experiments using MCF7 and HepG2 cell lines.
  • Quantitative real-time PCR and Western blotting to measure gene and protein expression.
  • siRNA silencing of ERα and c-Myb.
  • Luciferase reporter assays and in silico analysis.

Main Results:

  • Fulvestrant significantly upregulated UGT1A4 expression in a time- and concentration-dependent manner, dependent on ERα.
  • Fulvestrant also upregulated MRP1, MRP2, and MRP3 expression in tested cell lines.
  • UGT1A4 promoter variants and c-Myb binding influenced basal and fulvestrant-induced UGT1A4 activity.

Conclusions:

  • Fulvestrant influences the disposition of UGT1A4 substrates, potentially affecting drug efficacy.
  • UGT1A4 and MRPs play a significant role in the clinical outcomes of fulvestrant treatment.
  • These findings highlight potential drug-drug interactions and personalized medicine approaches.
Keywords:
AnastrozoleERαFulvestrantMRPsUGT1A4c-Myb

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