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Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells

Oncogene volume 21, pages 7077–7091 (2002)Cite this article

Abstract

Overexpression of the c-Jun proto-oncogene in MCF7 breast cancer cells results in a variety of phenotype changes related to malignant progression including increased motility and invasion. Concurrent with these phenotypic effects are changes in the expression of multiple gene targets. We previously demonstrated that expression of the SPARC/osteonectin gene, while undetectable in the MCF7 cell line, is highly induced in response to stable c-Jun overexpression (c-Jun/MCF7). Because the SPARC gene product is associated with tumor cell invasion in a variety of different cancers, we have examined its role in mediating the phenotypic changes induced by c-Jun in MCF7 cells. We found that antisense mediated suppression of SPARC dramatically inhibits both motility and invasion in this c-Jun/MCF7 model. In contrast, stable overexpression of SPARC in the parental MCF7 cell line is not sufficient to stimulate cell motility or invasion. Examination of the promoter region of the human SPARC gene reveals three non-canonical AP-1 sites. We demonstrate that one of these sites binds c-Jun/Fra1 heterodimers in vitro, but that this and the other AP-1 like sites are dispensable with respect to c-Jun stimulated SPARC promoter activation. Deletion analysis identified a region between −120 and −70 as a c-Jun responsive element sufficient to induce maximal promoter activation. This region does not contain any AP-1 sites but does mediate binding by SP1 ‘like’ complexes. Furthermore, this region is necessary for SP1/SP3 responsiveness in Drosophila SL2 cells. These results demonstrate that SPARC plays an important role in stimulating motility and the invasive behavior of c-Jun/MCF7 cells and that SPARC promoter activation by c-Jun appears to occur through an indirect mechanism.

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Acknowledgements

We thank Dr Janet Rinehart-Kim for technical assistance with the motility and invasion assays and for critical review of this manuscript. We are grateful to Dr Salvatore Oliviero for the gift of the pAC expression vectors. This work was supported in part by grants to TJ Bos and NIH R01CA51982 and the Thomas F and Kate Miller Jeffress Foundation and a grant from the Association pour la Recherche contre le Canter (ARC contract no 4398) to M Castellazzi.

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Authors and Affiliations

  1. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, 23501, VA, USA

    Joseph Briggs, Julie A Kerry & Timothy J Bos

  2. Unité de Virologie Humaine, INSERM U412, Ecole Normale Supérieure, 46 allée d'Italie, Lyon, Cedex 07, 69364, France

    Sandrine Chamboredon & Marc Castellazzi

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  1. Joseph Briggs
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Correspondence to Timothy J Bos.

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Briggs, J., Chamboredon, S., Castellazzi, M. et al. Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells. Oncogene 21, 7077–7091 (2002). https://doi.org/10.1038/sj.onc.1205857

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