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Molecular mechanisms for aberrant expression of the human breast cancer specific gene 1 in breast cancer cells: control of transcription by DNA methylation and intronic sequences

Oncogene volume 20, pages 5173–5185 (2001)Cite this article

Abstract

Breast cancer specific gene 1 (BCSG1), also referred as synuclein γ, is the third member of a neuronal protein family synuclein. BCSG1 is not expressed in normal breast tissues but highly expressed in advanced infiltrating breast carcinomas. When over expressed, BCSG1 significantly stimulates breast cancer metastasis. To elucidate the molecular mechanisms underlying the abnormal transcription of BCSG1 in breast cancer cells, in this study, we isolated a 2195 base pair fragment of human BCSG1 gene. This fragment includes 1 kb 5′-flanking region, exon 1, and intron 1. By analysing the promoter activity and the methylation status of the exon 1 region, we show that (1) Intron 1 plays critical roles in the control of BCSG1 gene transcription through cis-regulatory sequences that affect BCSG1 transcription in cell type-specific and cell type-nonspecific manners. (2) The activator protein-1 (AP-1) is functionally involved in BCSG1 transcription in breast cancer cells through its binding to an AP-1 motif located in the intron 1. (3) The exon 1 region of BCSG1 gene contains a CpG island that is unmethylated in BCSG1-positive SKBR-3 and T47D cells but densely methylated in BCSG1-negative MCF-7 cells. (4) Treating MCF-7 cells with a demethylating agent 5-Aza-2′-deoxycytidine specifically activated BCSG1 transcription. Thus, our results suggest that while the cellular content of transcription activators and repressors that interact with the cis-regulatory sequences present in the intron 1 contribute prominently to the tissue-specific expression of BCSG1, demethylation of exon 1 is an important factor responsible for the aberrant expression of BCSG1 in breast carcinomas.

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Abbreviations

AP-1:

activator protein 1

5-aza-C:

5-Aza-2′-deoxycytidine

BCSG1:

breast cancer specific gene 1

EMSA:

electrophoresis mobility shift assay

FBS:

fetal bovine serum

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

OM:

oncostatin M

RE1:

repressive element 1

RE2:

repressive element 2

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Acknowledgements

We thank Ms Lisa French at the Sanger Centre for providing the genomic clone, Dr Benoit I Giasson at University of Pennsylvania School of Medicine for providing the anti-BCSG1 polyclonal antibodies, and Dr Fredric B Kraemer for his critical review of the manuscript. This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), by grant (1RO1CA83648-01) from National Cancer Institute, and by grant (BC990960) from the United States Army Medical Research and Development Command.

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Authors and Affiliations

  1. VA Palo Alto Health Care System, Palo Alto, CA 94304, California, USA

    AiPing Lu, Anu Gupta, Cong Li, Thomas E Ahlborn & Jingwen Liu

  2. VA Medical Center, Boise, ID 83702, Idaho, USA

    YongSheng Ma

  3. Long Island Jewish Medical Center, New Hyde Park, NY 11042, New York, USA

    Eric Y Shi

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  1. AiPing Lu
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Correspondence to Jingwen Liu.

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Lu, A., Gupta, A., Li, C. et al. Molecular mechanisms for aberrant expression of the human breast cancer specific gene 1 in breast cancer cells: control of transcription by DNA methylation and intronic sequences. Oncogene 20, 5173–5185 (2001). https://doi.org/10.1038/sj.onc.1204668

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