AKT Alters Genome-Wide Estrogen Receptor alpha Binding and Impacts Estrogen Signaling in Breast Cancer

作者：Bhat Nakshatri Poornima; Wang Guohua; Appaiah Hitesh; Luktuke Nikhil; Carroll Jason S; Geistlinger Tim R; Brown Myles; Badve Sunil; Liu Yunlong; Nakshatri Harikrishna^*

来源：Molecular and Cellular Biology, 2008, 28(24): 7487-7503.

DOI：10.1128/MCB.00799-08

Estrogen regulates several biological processes through estrogen receptor alpha (ER alpha) and ER beta. ER beta-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 similar to 60% overlap. In both cell types, similar to 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 beta (TGF-beta), NF-kappa B, 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 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.

• 出版日期2008-12-15