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Originally published In Press as doi:10.1074/jbc.M201060200 on June 18, 2002

J. Biol. Chem., Vol. 277, Issue 35, 31364-31372, August 30, 2002
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Blockade of AP1 Transactivation Abrogates the Abnormal Expression of Breast Cancer-specific Gene 1 in Breast Cancer Cells*

AiPing Lu, Fang Zhang, Anu Gupta, and Jingwen LiuDagger

From the Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, California 94304

Breast cancer-specific gene 1 (BCSG1) is not expressed in normal breast tissue but is highly expressed in the vast majority of invasive and metastatic breast carcinomas. When over-expressed, BCSG1 significantly stimulates the proliferation and invasion of breast cancer cells. The accumulated evidence suggests that the aberrant expression of BCSG1 in breast carcinomas is caused by transcriptional activation of the BCSG1 gene. However, the transcription factors that activate BCSG1 transcription have not been identified. In this study, we extensively investigated the role of AP1 in BCSG1 expression in breast cancer cells. We demonstrate that there are two closely located AP1 binding sites residing in the first intron of the BCSG1 gene. Mutation of either AP1 motif on the BCSG1 promoter constructs markedly reduces the promoter activity. We further show that 12-O-tetradecanoylphorbol-13-acetate (TPA) increases BCSG1 mRNA expression and up-regulates BCSG1 promoter activity through the intronic AP1 sites. The effect of TPA on BCSG1 transcription is also demonstrated under in vivo conditions in intact cells by using chromatin immunoprecipitation assays that show the TPA-induced binding of c-Jun to the chromatin region encompassing the intronic AP1 sites. Finally, to examine the direct effect of AP1 transactivation on BCSG1 expression, we established stable cell lines of T47D that express the dominant negative mutant of c-Jun, TAM67. RT-PCR and Western blot analyses demonstrated that levels of BCSG1 mRNA and protein in TAM67 transfectants were drastically reduced as compared with mock-transfected cells. Furthermore, inhibition of BCSG1 expression by blocking AP1 transactivation produced a similar repressive effect on cell growth as that by expressing BCSG1 antisense mRNA. We show that the anchorage-independent growth of T47D cells expressing either TAM67 or BCSG1 antisense mRNA is significantly inhibited. Taken together, we provide strong evidence that AP1 plays an overriding role in the transcription of the BCSG1 gene and that blockade of AP1 transactivation down-regulates BCSG1 expression and suppresses tumor phenotype.

* This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), by Grant 1RO1CA83648-01 from the National Cancer Institute, and by Grant BC010046 from the United States Army Medical Research and Materiel Command.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304. Tel.: 650-493-5000, ext. 64411; Fax: 650-849-0251; E-mail: Jingwen.Liu@med.va.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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