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Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor γ in the MCF-7 breast cancer cell line

Oncogene volume 22, pages 5446–5450 (2003)Cite this article

Abstract

BRCA1 has been linked to the genetic susceptibility of a majority of familial breast and ovarian cancers. Several lines of evidence indicate that BRCA1 is a tumor suppressor and its expression is downregulated in sporadic breast and ovarian cancer cases. Therefore, the identification of genes involved in the regulation of BRCA1 gene expression might lead to new insights into the pathogenesis and treatment of these tumors. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily that has well-established roles in the regulation of adipocyte development and glucose homeostasis. More recently, it has been shown that ligands of PPARγ have a potent antitumorigenic activity in breast cancer cells. In the present study we have found that two distinct ligands of PPARγ; 15-deoxy-Δ-12,14-prostaglandin J2 (15dPG-J2) and rosiglitazone, increase the levels of BRCA1 protein in human MCF-7 breast cancer cells. Immunofluorescence microscopy analysis showed that, after treatment with 15dPG-J2, the BRCA1 protein is mainly localized in the nucleus. Functional analysis by transient transfection of different 5′-flanking region fragments, as well as gel mobility shift assays and mutagenic analysis, suggests that the effects of 15dPG-J2 and rosiglitazone are mediated through a functional DR1 located between the nucleotides −241 and −229, which is a canonical PPARγ type response element. Our data suggest that PPARγ is a crucial gene regulating BRCA1 gene expression and might therefore be important for the BRCA1 regulatory pathway involved in the pathogenesis of sporadic breast and ovarian cancer.

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Acknowledgements

This work has been supported by grants from the Dirección General de Enseñanza Superior e Investigación Científica, Grants BMC2001-2342 (APC) and PM99-0057 (AS) and by the Comunidad de Madrid, Grant 08.5/0078/2000 (AS). MP is a fellow of the Fondo de Investigaciones Sanitarias de la Seguridad Social.

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Author notes

  1. Claudia Cocca

    Present address: Departamento de Radioisótopos, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Spain

    Miguel Pignatelli, Claudia Cocca & Ana Perez-Castillo

  2. Departamento de Bioquímica y Biología Molecular. Facultad de Medicina, Universidad Complutense de Madrid, Spain

    Angel Santos

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  1. Miguel Pignatelli
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Correspondence to Ana Perez-Castillo.

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Pignatelli, M., Cocca, C., Santos, A. et al. Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor γ in the MCF-7 breast cancer cell line. Oncogene 22, 5446–5450 (2003). https://doi.org/10.1038/sj.onc.1206824

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