Molecular and Cellular Biochemistry

, Volume 372, Issue 1, pp 249–256

PPARγ antagonist GW9662 induces functional estrogen receptor in mouse mammary organ culture: potential translational significance

  • Rajendra G. Mehta
  • Xinjian Peng
  • Sarbani Roy
  • Michael Hawthorne
  • Amit Kalra
  • Fatouma Alimirah
  • Rajeshwari R. Mehta
  • Levy Kopelovich
Article

DOI: 10.1007/s11010-012-1466-9

Cite this article as:
Mehta, R.G., Peng, X., Roy, S. et al. Mol Cell Biochem (2013) 372: 249. doi:10.1007/s11010-012-1466-9

Abstract

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in regulating metabolism, including interaction with the estrogen receptor-α (ERα). Significantly, PPARγ activity can be modulated by small molecules to control cancer both in vitro and in vivo (Yin et al., Cancer Res 69:687–694, 2009). Here, we evaluated the effects of the PPARγ agonist GW7845 and the PPARγ antagonist GW9662 on DMBA-induced mammary alveolar lesions (MAL) in a mouse mammary organ culture. The results were as follows: (a) the incidence of MAL development was significantly inhibited by GW 7845 and GW 9662; (b) GW9662 but not GW7845, in the presence of estradiol, induced ER and PR expression in mammary glands and functional ERα in MAL; (c) while GW9662 inhibited expression of adipsin and ap2, GW 7845 enhanced expression of these PPARγ-response genes; and (d) Tamoxifen caused significant inhibition of GW9662 treated MAL, suggesting that GW9662 sensitizes MAL to antiestrogen treatment, presumably through rendering functional ERα and induction of PR. The induction of ERα by GW9662, including newer analogs, may permit use of anti-ER strategies to inhibit breast cancer in ER− patients.

Keywords

Organ cultureEstrogen receptorPPARγMammary gland

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Rajendra G. Mehta
    • 1
  • Xinjian Peng
    • 1
  • Sarbani Roy
    • 1
  • Michael Hawthorne
    • 1
  • Amit Kalra
    • 1
  • Fatouma Alimirah
    • 1
  • Rajeshwari R. Mehta
    • 1
  • Levy Kopelovich
    • 2
  1. 1.IIT Research InstituteChicagoUSA
  2. 2.Chemoprevention Agent Development Research Group, Division of Cancer PreventionNational Cancer InstituteBethesdaUSA