Therapeutic administration of
glucocorticoids (GCs) is frequently used as add-on
chemotherapy for palliative purposes during
breast cancer treatment. Recent studies have shown that GC treatment induces microRNA-708 in
ovarian cancer cells, resulting in impaired
tumor cell proliferation and
metastasis. However, the regulatory functions of GCs on miR-708 and its downstream target genes in human
breast cancer cells (BCCs) are poorly understood. In this study, we found that treatment with either the synthetic GC
dexamethasone (DEX) or the natural GC mimic,
antcin A (ATA) significantly increased miR-708 expression by transactivation of
glucocorticoid receptor alpha (GRα) in MCF-7 and MDA-MB-231 human BCCs. Induction of miR-708 by GR agonists resulted in inhibition of cell proliferation, cell-cycle progression, cancer stem cell (CSC)-like phenotype and
metastasis of BCCs. In addition, GR agonist treatment or miR-708 mimic transfection remarkably inhibited IKKβ expression and suppressed
nuclear factor-kappaB (NF-κB) activity and its downstream target genes, including COX-2, cMYC,
cyclin D1,
Matrix metalloproteinase (MMP)-2, MMP-9, CD24, CD44 and increased p21CIP1 and p27KIP1 that are known to be involved in proliferation, cell-cycle progression,
metastasis and CSC marker
protein. BCCs xenograft models indicate that treatment with GR agonists significantly reduced
tumor growth, weight and volume. Overall, our data strongly suggest that GR agonists induced miR-708 and downstream suppression of NF-κB signaling, which may be applicable as a novel therapeutic intervention in
breast cancer treatment.