Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer

Zhong Chen, Xun Lan, Dayong Wu, Benjamin Sunkel, Zhenqing Ye, Jiaoti Huang, Zhihua Liu, Steven K. Clinton, Victor X. Jin, Qianben Wang

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37 Scopus citations

Abstract

Glucocorticoids (GCs) have been widely used as coadjuvants in the treatment of solid tumours, but GC treatment may be associated with poor pharmacotherapeutic response or prognosis. The genomic action of GC in these tumours is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC)-regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and are associated with unfavourable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR.

Original languageEnglish (US)
Article number8323
JournalNature communications
Volume6
DOIs
StatePublished - Sep 16 2015

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Chen, Z., Lan, X., Wu, D., Sunkel, B., Ye, Z., Huang, J., Liu, Z., Clinton, S. K., Jin, V. X., & Wang, Q. (2015). Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer. Nature communications, 6, [8323]. https://doi.org/10.1038/ncomms9323