Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

Breast Cancer Research

Eva C Bonefeld-Jørgensen¹  Irene Gjermandsen¹  Thomas Rattenborg¹ 

[1] Unit of Environmental Biotechnology, Department of Environmental and Occupational Medicine, University of Aarhus, Denmark

关键词: toxaphene;    tetrachlorodibenzo-p-dioxin;    polychlorinated biphenyls;    estrogen receptor;    BRCA1;   

Others  :  1118822
DOI  :  10.1186/bcr461

 received in 2002-03-28, accepted in 2002-07-04,  发布年份 2002

【 摘 要 】

Background

Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter the expression of BRCA1.

Methods

Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153 and PCB#180]) was measured by a reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold concentration range was analyzed in MCF-7, and the results were supported by northern blot analysis of BRCA1 mRNA using the highest concentrations of the chemicals.

Results

All three polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin reduced 17β-estradiol (E2)-induced expression as well as basal reporter gene expression in both cell lines, whereas northern blot analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in MCF-7 cells. Toxaphene, like E2, induced BRCA1 expression in MCF-7.

Conclusion

The present study shows that some POCs have the capability to alter the expression of the tumor suppressor gene BRCA1 without affecting the cell-cycle control protein p21^Waf/Cip1. Some POCs therefore have the potential to affect breast cancer risk.

【 授权许可】

   
2002 2002 Rattenborg et al., licensee BioMed Central Ltd

【 图 表 】

Figure 1.

Figure 3.

Figure 2.

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