title: Dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced prostate carcinogenesis in CYP1A-humanized mice.
abstract: To develop a relevant mouse model for prostate cancer prevention research, we administered a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), to CYP1A-humanized mice. In comparison with mouse Cyp1a2, human CYP1A2 preferentially activates PhIP to a proximate carcinogen. Following a single oral dose of PhIP (200 mg/kg body weight), we observed inflammation, atrophy of acini, low-grade prostatic intraepithelial neoplasia (PIN; after 20 weeks), and high-grade PIN (HgPIN; after 30 to 50 weeks) in dorsolateral, ventral, and coagulating anterior prostate glands of these mice. These lesions were androgen receptor positive and featured the loss of expression of the basal cell marker p63 and the tumor suppressor PTEN. Similar to human prostate carcinogenesis, glutathione S-transferase P1 (GSTP1) expression was lost or partially lost in HgPIN. E-Cadherin expression was also lost in HgPIN. The expression of DNA methyltransferase 1 was elevated, possibly to enhance promoter hypermethylation for the silencing of GSTP1 and E-cadherin. Prostate carcinogenesis was promoted by a high-fat stress diet, resulting in HgPIN that developed earlier and in advanced lesions displayed features consistent with carcinoma in situ. This dietary carcinogen-induced prostate cancer model, recapitulating important features of early human prostate carcinogenesis, constitutes a new experimental system for prostate cancer research.
authors.affiliation: Department of Chemical Biology, Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Guangxun
authors.initials: G
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Anna B
authors.initials: AB
authors.lastname: Liu
authors.forename: Connie
authors.initials: C
authors.lastname: Cheung
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.forename: Maarten C
authors.initials: MC
authors.lastname: Bosland
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019048:Prostatic Intraepithelial Neoplasia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*
chemical_list: D015820:Cadherins; D002273:Carcinogens; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019388:Cytochrome P-450 CYP1A2; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse