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03-15-2006, 05:05 AM

1: Chem Res Toxicol. 2005 Oct;18(10):1528-36. Links

PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor.

Bennion BJ, Cosman M, Lightstone FC, Knize MG, Montgomery JL, Bennett LM, Felton JS, Kulp KS.

Biosciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94551, and Center for Cancer Research, NCI, NIH, 31 Center Drive, 31/3A11, Bethesda, Maryland 20892.

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, N(2)()-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 N(2)()-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.

PMID: 16533016 [PubMed - in process]

03-15-2006, 05:05 AM	#1
Lani Guest Posts: n/a	breast cancer related to the consumption of well-done meat? 1: Chem Res Toxicol. 2005 Oct;18(10):1528-36. Links PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor. Bennion BJ, Cosman M, Lightstone FC, Knize MG, Montgomery JL, Bennett LM, Felton JS, Kulp KS. Biosciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94551, and Center for Cancer Research, NCI, NIH, 31 Center Drive, 31/3A11, Bethesda, Maryland 20892. 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, N(2)()-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 N(2)()-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. PMID: 16533016 [PubMed - in process]