Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Our clinically relevant finding is that glucocorticoids block estrogen (E-2)-induced apoptosis in long-term E-2-deprived (LTED) breast cancer cells. However, the mechanism remains undear. Here, we demonstrated that E-2 widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), IL6, and TNF alpha in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNF alpha expression. Furthermore, dexamethasone was synergistic or additive with E-2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNF alpha expression induced by E-2 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 E-2, but it had no inhibitory effects on inositol-requiring protein 1 alpha (IRE1 alpha) expression increased by E-2. Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1 alpha-mediated degradation of PI3K/Akt-associated signal pathways activated by E-2. Unexpectedly, activated GR preferentially repressed nuclear factor-kappa B (NF-kappa B) DNA-binding activity and expression of NF-kappa B-dependent gene TNF alpha, induced by E-2, leading to the blockade of E-2-induced apoptosis. Together, these data suggest that trans-suppression of NF-kappa B by CR in the nucleus is a fundamental mechanism thereby blocking E-2-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 E-2-induced apoptosis in patients with aromatase inhibitor-resistant breast cancer.