AKT alters genome-wide estrogen receptor alpha binding and impacts estrogen signaling in breast cancer.
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.
Department of Surgery, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202, USA.
Poornima
P
Bhat-Nakshatri
Guohua
G
Wang
Hitesh
H
Appaiah
Nikhil
N
Luktuke
Jason S
JS
Carroll
Tim R
TR
Geistlinger
Myles
M
Brown
Sunil
S
Badve
Yunlong
Y
Liu
Harikrishna
H
Nakshatri
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000502:physiology*
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt