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

Poornima Bhat-Nakshatri, Guohua Wang, Hitesh Appaiah, Nikhil Luktuke, Jason S. Carroll, Tim R. Geistlinger, Myles Brown, Sunil Badve, Yunlong Liu, Harikrishna Nakshatri

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERα. ERα-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 ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα 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 β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

Original languageEnglish (US)
Pages (from-to)7487-7503
Number of pages17
JournalMolecular and cellular biology
Volume28
Issue number24
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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