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 unclear. Here, we demonstrated that E(2) widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone (Dex) upregulated FADS1 and IL-6 but downregulated TNFα expression. Furthermore, Dex was synergistic or additive with E(2) in upregulating FADS1 and IL-6 expression, whereas it selectively and constantly suppressed TNFα expression induced by E(2) in LTED breast cancer cells. Regarding regulation of endoplasmic reticulum stress, Dex 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 (IRE1α) expression increased by E(2). Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that Dex could not reverse IRE1α-mediated degradation of phosphoinositide 3-kinase (PI3K)/Akt-associated signal pathways activated by E(2). Unexpectedly, activated GR preferentially repressed nuclear factor-κB (NF-κB) DNA-binding activity and expression of NF-κB-dependent gene TNFα induced by E(2), leading to the blockade of E(2)-induced apoptosis. Together, these data suggest that trans-suppression of NF-κB by GR 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 aromatase inhibitor-resistant breast cancer patients.