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J. Biol. Chem., Vol. 281, Issue 21, 14654-14662, May 26, 2006

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BRCA1 Modulates Xenobiotic Stress-inducible Gene Expression by Interacting with ARNT in Human Breast Cancer Cells^*

Hyo Jin Kang, Hee Jeong Kim, Sang Keun Kim, Robert Barouki^¶, Chi-Heum Cho^||, Kum Kum Khanna^**, Eliot M. Rosen, and Insoo Bae¹

From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea, ^¶INSERM Unit 490, Universite Rene Descartes, 45 Rue des Saints Peres, 75 270 Cedex 06, Paris, France, ^||Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, 194 Dongsan-Dong, Choong-Ku, Daegu, Korea, and ^**Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Queensland 4029 Australia

Previously, we have reported that BRCA1 regulates the expression of various classes of genes, including genes involved in xenobiotic stress responses (Bae, I., Fan, S., Meng, Q., Rih, J. K., Kim, H. J., Kang, H. J., Xu, J., Goldberg, I. D., Jaiswal, A. K., and Rosen, E. M. (2004) Cancer Res. 64, 7893–7909). In the present study, we have investigated the effects of BRCA1 on xenobiotic stress-inducible gene expression. In response to aryl hydrocarbon receptor (AhR) ligands, cytoplasmic AhR becomes activated and then translocates to the nucleus where it forms a complex with the aryl hydrocarbon receptor nuclear translocator (ARNT). Subsequently, the AhR·ARNT complex binds to the enhancer or promoter of genes containing a xenobiotic stress-responsive element and regulates the expression of multiple target genes including cytochrome P450 subfamily polypeptide 1 (CYP1A1). In this study, we have found that endogenous and overexpressed exogenous wild-type BRCA1 affect xenobiotic stress-induced CYP1A1 gene expression. Using a standard chromatin immunoprecipitation assay, we have demonstrated that BRCA1 is recruited to the promoter regions of CYP1A1 and CYP1B1 along with ARNT and/or AhR following xenobiotic exposure. Our findings suggest that BRCA1 may be physiologically important for mounting a normal response to xenobiotic insults and that it may function as a coactivator for ARNT activity. Using immunoprecipitation, Western blotting, and glutathione S-transferase capture assays, a xenobiotic-independent interaction between BRCA1 and ARNT has been identified, although it is not yet known whether this is a direct or indirect interaction. We have also found that the inducibility of CYP1A1 and CYP1B1 transcripts following xenobiotic stress was significantly attenuated in BRCA1 knockdown cells. This reduced inducibility is associated with an altered stability of ARNT and was almost completely reversed in cells transfected with an ARNT expression vector. Finally, we have found that xenobiotic (TCDD) treatments of breast cancer cells containing reduced levels of BRCA1 cause the transcription factor ARNT to become unstable.

Received for publication, February 21, 2006

^* This research was supported by a United States Army Idea Award (DAMD17-02-1-0525) (to I. B.), American Cancer Society Grant IRG 97-152-13 (to I. B.), NIEHS, National Institutes of Health (ES014440-01) (to I. B.), the Susan G. Komen Breast Cancer Foundation (BCTR119906) (to I. B.), and in part by NCI, National Institutes of Health (CA080000) (to E. M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Oncology, Lombardi Comprehensive Cancer Ctr., Georgetown University, 3970 Reservoir Rd., NW, Washington, DC 20057-1469. Tel.: 202-687-5267; Fax: 202-687-7256; E-mail: ib42{at}georgetown.edu.

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