Corepressors LCoR and KAP1 form a complex with the transcription factor ZBRK1 to silence FGF2 gene expression and maintain breast cancer cell viability

Abstract

Through the use of a yeast two‐hybrid screen, we have a found a novel interaction between the C‐terminal domain of the transcriptional coregulator ligand‐dependent corepressor (LCoR) and the transcriptional corepressor Kruppel‐associated protein‐1 (KAP‐1). These transcriptional regulators associate with the transcription factor ZBRK1 and repress the expression of the Fibroblast Growth Factor 2 (FGF2) and Growth Arrest and DNA‐Damage‐inducible alpha (GADD45A) genes in breast cancer cell lines. Remarkably, ablation of ZBRK1, KAP‐1, or LCoR expression led to apoptotic death of specific breast cancer cells. This loss of viability could be partly rescued by simultaneous knockdown of FGF2, which abrogated the elevated FGF2 production in ZBRK1‐, KAP‐1, or LCoR‐deficient cells. Studies show that more malignant phenotypes in breast cancer are associated with loss of FGF2 expression, although the mechanism of this loss is poorly understood. We propose that ZBRK1, KAP‐1, and LCoR form a transcriptional complex that silences expression of genes, in particular FGF2, which enhances specific breast cancer cell viability. Research funded by the Canadian Institutes of Health Research (CIHR).