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 and Qianben Wang ()
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Zhong Chen: Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine
Xun Lan: Stanford University
Dayong Wu: Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine
Benjamin Sunkel: Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine
Zhenqing Ye: University of Texas Health Science Center at San Antonio
Jiaoti Huang: Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
Zhihua Liu: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Steven K. Clinton: Ohio State University College of Medicine
Victor X. Jin: University of Texas Health Science Center at San Antonio
Qianben Wang: Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9323

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