Regulation of αB-crystallin gene expression by the transcription factor Ets1 in breast cancer
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Recent studies indicate that the small heat shock protein αB-crystallin is expressed in poor prognosis basal-like breast tumors and likely contributes to their aggressive phenotype. However, the mechanisms underlying the deregulated expression of αB-crystallin in basal-like tumors are poorly understood. Using a bioinformatics approach, we identified a putative DNA binding motif in the human αB-crystallin promoter for the proto-oncogene Ets1, a member of the ETS transcription factor family that bind to DNA at palindromic ETS-binding sites (EBS). Here we demonstrate that ectopic expression of Ets1 activates the αB-crystallin promoter by an EBS-dependent mechanism and increases αB-crystallin protein levels, while silencing Ets1 reduces αB-crystallin promoter activity and protein levels. Chromatin immunoprecipitation analyses showed that endogenous Ets1 binds to the αB-crystallin promoter in basal-like breast cancer cells in vivo. Interrogation of publically available gene expression data revealed that Ets1 is expressed in human basal-like breast tumors and is associated with poor survival. Collectively, our results point to a previously unrecognized link between the oncogenic transcription factor Ets1 and αB-crystallin in basal-like breast cancer.
KeywordsαB-crystallin Ets1 Molecular chaperone Basal-like breast cancer Gene regulation
We thank Drs. M. Zhou and M. Sharon Stack for plasmids. This work was supported by NIH grants R01CA097198 (VLC), R21CA125181 (VLC) and T32GM08061 (JDB), and by the Breast Cancer Research Foundation (VLC).
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