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Molecular and Cellular Biology, December 2008, p. 7487-7503, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00799-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

AKT Alters Genome-Wide Estrogen Receptor {alpha} Binding and Impacts Estrogen Signaling in Breast Cancer{triangledown} ,{dagger}

Poornima Bhat-Nakshatri,1 Guohua Wang,2 Hitesh Appaiah,1 Nikhil Luktuke,1 Jason S. Carroll,3,{ddagger} Tim R. Geistlinger,3 Myles Brown,3 Sunil Badve,4 Yunlong Liu,2 and Harikrishna Nakshatri1,5,6*

Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202,1 Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202,2 Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,3 Departments of Pathology and Internal Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202,4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202,5 Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 462026

Received 16 May 2008/ Returned for modification 19 June 2008/ Accepted 27 September 2008

Estrogen regulates several biological processes through estrogen receptor {alpha} (ER{alpha}) and ERβ. ER{alpha}-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 ER{alpha} binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ER{alpha} binding sites, respectively, with ~60% overlap. In both cell types, ~40% of estrogen-regulated genes associate with ER{alpha} 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-{kappa}B, 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 ER{alpha} DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ER{alpha} binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ER{alpha}-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ER{alpha}-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

* Corresponding author. Mailing address: R4-202, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202. Phone: (317) 278-2238. Fax: (317) 274-0396. E-mail: hnakshat{at}iupui.edu

{triangledown} Published ahead of print on 6 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom.

Molecular and Cellular Biology, December 2008, p. 7487-7503, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00799-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bhat-Nakshatri, P., Wang, G., Collins, N. R., Thomson, M. J., Geistlinger, T. R., Carroll, J. S., Brown, M., Hammond, S., Srour, E. F., Liu, Y., Nakshatri, H. (2009). Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res 37: 4850-4861 [Abstract] [Full Text]  
  • Lupien, M., Brown, M. (2009). Cistromics of hormone-dependent cancer. Endocr Relat Cancer 16: 381-389 [Abstract] [Full Text]  


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