PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor

Chem Res Toxicol. 2005 Oct;18(10):1528-36. doi: 10.1021/tx0501031.


Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here, we describe our work with the human estrogen receptor alpha (ERalpha), the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, and IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We demonstrate both by computational docking and NMR analysis that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. In vitro assays show that PhIP, in contrast to the other heterocyclic amines, increases cell proliferation in MCF-7 human breast cancer cells and activates the ERalpha receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ERalpha activation. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding, Competitive
  • Carcinogens / toxicity*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Estradiol / metabolism
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / drug effects*
  • Estrogen Receptor alpha / metabolism
  • Furans / toxicity
  • Hot Temperature
  • Humans
  • Imidazoles / toxicity*
  • Meat*
  • Quinoxalines / toxicity


  • 2-amino-(1,6-dimethylfuro(3,2-e)imidazo(4,5-b))pyridine
  • Carcinogens
  • Estrogen Receptor alpha
  • Furans
  • Imidazoles
  • Quinoxalines
  • Estradiol
  • 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine