This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shan, L. Articles by Snyderwine, E. G. Search for Related Content PubMed PubMed Citation Articles by Shan, L. Articles by Snyderwine, E. G.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Modulates Lactogenic Hormone-mediated Differentiation and Gene Expression in HC11 Mouse Mammary Epithelial Cells

Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [L. S., S. A. R., E. G. S.], and Department of Pathology, Medical College of Ohio, Toledo, Ohio 43614-5806 [H. A. J. S.]

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary gland carcinogen in cooked meat. Using the HC11 mouse mammary epithelial cell line, a well-characterized model for hormone-mediated differentiation, we examined whether PhIP altered the expression of genes regulated by lactogenic hormones dexamethasone, insulin, and prolactin (DIP). When HC11-Lux cells (stably transfected with a ß-casein promoter luciferase construct) were cultured in DIP-containing medium, PhIP (100 µM) enhanced luciferase activity 11-fold over that observed in DIP medium alone. The effect of PhIP on augmenting luciferase activity was observed only when lactogenic hormones were included in the medium. Expression of the endogenous ß-casein gene was also higher in HC11 cells treated with PhIP in hormone-enriched medium. With the increased expression of ß-casein gene, the level of phospho-signal transducer and activator of transcription 5A (phospho-STAT5A), the transcription factor regulating ß-casein gene expression, was elevated in PhIP-exposed HC11 cells. AG490, a Janus kinase 2 (JAK2)-specific inhibitor, blocked the effect of PhIP on ß-casein gene expression. PhIP-treated cells also showed higher expression of Bcl-2 and lower expression of Bax, consistent with a possible antiapoptotic action of PhIP. The findings indicate that PhIP modulates lactogenic hormone-mediated gene expression in mammary epithelial cells, apparently via enhanced phosphorylation of STAT5A. The findings have implications for a novel mechanism of action of the mammary gland carcinogen PhIP.

This article has been cited by other articles:

				S. N. Lauber and N. J. Gooderham The Cooked Meat Derived Genotoxic Carcinogen 2-Amino-3-Methylimidazo[4,5-b]Pyridine Has Potent Hormone-Like Activity: Mechanistic Support for a Role in Breast Cancer Cancer Res., October 1, 2007; 67(19): 9597 - 9602. [Abstract] [Full Text] [PDF]

				L. Shan, M. Yu, H. A.J. Schut, and E. G. Snyderwine Susceptibility of Rats to Mammary Gland Carcinogenesis by the Food-Derived Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine (PhIP) Varies with Age and Is Associated with the Induction of Differential Gene Expression Am. J. Pathol., July 1, 2004; 165(1): 191 - 202. [Abstract] [Full Text] [PDF]

				L. Shan, M. Yu, C. Qiu, and E. G. Snyderwine Id4 Regulates Mammary Epithelial Cell Growth and Differentiation and Is Overexpressed in Rat Mammary Gland Carcinomas Am. J. Pathol., December 1, 2003; 163(6): 2495 - 2502. [Abstract] [Full Text]

				Z. Hou, S. Srivastava, M. J. Mistry, M. P. Herbst, J. P. Bailey, and N. D. Horseman Two Tandemly Linked Interferon-{gamma}-Activated Sequence Elements in the Promoter of Glycosylation-Dependent Cell Adhesion Molecule 1 Gene Synergistically Respond to Prolactin in Mouse Mammary Epithelial Cells Mol. Endocrinol., October 1, 2003; 17(10): 1910 - 1920. [Abstract] [Full Text] [PDF]