Journal Article

Interplay between AP-1 and estrogen receptor α in regulating gene expression and proliferation networks in breast cancer cells

Karin Dahlman-Wright, Yichun Qiao, Philip Jonsson, Jan-Åke Gustafsson, Cecilia Williams and Chunyan Zhao

in Carcinogenesis

Volume 33, issue 9, pages 1684-1691
Published in print September 2012 | ISSN: 0143-3334
Published online July 2012 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgs223
Interplay between AP-1 and estrogen receptor α in regulating gene expression and proliferation networks in breast cancer cells

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Estrogen receptor α (ERα) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERα can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that c-Fos is a fundamental factor for ERα-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent proproliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERα can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross talk between AP-1 and estrogen signaling, we identify a novel ERα/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-β), which is overexpressed in ERα-positive breast cancer tissues. Knockdown of PKIB results in robust growth suppression of breast cancer cells. Collectively, our findings support c-Fos as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.

Abbreviations:

AP-1

activator protein-1

BrdU

bromodeoxyuridine

ChIP

chromatin immunoprecipitation

E2

17β-estradiol;

ERα

estrogen receptor α

GO

gene ontology

PKIB

cAMP-dependent protein kinase inhibitor-β

siRNA

small interfering RNA

TPA

12-O-tetradecanoylphorbol-13-acetate

Journal Article.  5465 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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