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Mol Cell Biol. 2008 Dec;28(24):7487-503. doi: 10.1128/MCB.00799-08. Epub 2008 Oct 6.

AKT alters genome-wide estrogen receptor alpha binding and impacts estrogen signaling in breast cancer.

Author information

1
Department of Surgery, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202, USA.

Abstract

Estrogen regulates several biological processes through estrogen receptor alpha (ERalpha) and ERbeta. ERalpha-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERalpha binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERalpha binding sites, respectively, with approximately 60% overlap. In both cell types, approximately 40% of estrogen-regulated genes associate with ERalpha binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor beta (TGF-beta), NF-kappaB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-beta treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERalpha DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERalpha binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERalpha-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERalpha-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

PMID:
18838536
PMCID:
PMC2593438
DOI:
10.1128/MCB.00799-08
[Indexed for MEDLINE]
Free PMC Article

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