Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived...

Our clinically relevant finding is that glucocorticoids block estrogen (E₂)-induced apoptosis in long-term E₂-deprived (LTED) breast cancer cells. However, the mechanism remains unclear. Here, we demonstrated that E₂ widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), IL6, and TNFα in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFα expression. Furthermore, dexamethasone was synergistic or additive with E₂ in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFα expression induced by E₂ in LTED breast cancer cells. Regarding regulation of endoplasmic reticulum stress, dexamethasone effectively blocked activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by E₂, but it had no inhibitory effects on inositol-requiring protein 1 alpha (IRE1α) expression increased by E₂ Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1α-mediated degradation of PI3K/Akt-associated signal pathways activated by E₂ Unexpectedly, activated GR preferentially repressed nuclear factor-κB (NF-κB) DNA-binding activity and expression of NF-κB-dependent gene TNFα induced by E₂, leading to the blockade of E₂-induced apoptosis. Together, these data suggest that trans-suppression of NF-κB by GR in the nucleus is a fundamental mechanism thereby blocking E₂-induced apoptosis in LTED breast cancer cells. This study provided an important rationale for restricting the clinical use of glucocorticoids, which will undermine the beneficial effects of E₂-induced apoptosis in patients with aromatase inhibitor-resistant breast cancer.