TY - JOUR
T1 - Suppression of nuclear factor-kB by glucocorticoid receptor blocks estrogen-induced apoptosis in estrogen-deprived breast cancer cells
AU - Fan, Ping
AU - Siwak, Doris R.
AU - Abderrahman, Balkees
AU - Agboke, Fadeke A.
AU - Yerrum, Smitha
AU - Jordan, V. Craig
N1 - Funding Information:
This work was supported by a Department of Defense Breast Program Center of Excellence Award W81XWH-06-1-0590 (to V.C. Jordan), the NIH/NCI under award number P30-CA016672 (to P.W. Pisters), Susan G. Komen for the Cure Foundation under award number SAC100009 (to V.C. Jordan), and Cancer Prevention Research Institute of Texas (CPRIT) for the STARs and STARs plus Awards (to V.C. Jordan). V.C. Jordan thanks the George and Barbara Bush Foundation for Innovative Cancer Research and the benefactors of the Dallas/ Fort Worth Living Legend Chair of Cancer Research for their generous support. TheauthorsthankDon Norwood intheDepartmentofScientificPublicationsat MD Anderson Cancer Center for editing the manuscript. We also thank the MD Anderson's Characterized Cell Line Core for validating cell lines, which is funded by NCI #CA16672.
Funding Information:
This work was supported by a Department of Defense Breast Program Center of Excellence Award W81XWH-06-1-0590 (to V.C. Jordan), the NIH/NCI under award number P30-CA016672 (to P.W. Pisters), Susan G. Komen for the Cure Foundation under award number SAC100009 (to V.C. Jordan), and Cancer Prevention Research Institute of Texas (CPRIT) for the STARs and STARs plus Awards (to V.C. Jordan). V.C. Jordan thanks the George and Barbara Bush Foundation for Innovative Cancer Research and the benefactors of the Dallas/ Fort Worth Living Legend Chair of Cancer Research for their generous support. The authors thank Don Norwood in the Department of Scientific Publications at MD Anderson Cancer Center for editing the manuscript. We also thank the MD Anderson's Characterized Cell Line Core for validating cell lines, which is funded by NCI #CA16672.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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 TNFa in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFa expression. Furthermore, dexamethasone was synergistic or additive with E2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFa 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 (IRE1a) expression increased by E2. Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1a-mediated degradation of PI3K/Akt-associated signal pathways activated by E2. Unexpectedly, activated GR preferentially repressed nuclear factor-kB (NF-kB) DNA-binding activity and expression of NF-kB–dependent gene TNFa induced by E2, leading to the blockade of E2-induced apoptosis. Together, these data suggest that trans-suppression of NF-kB 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.
AB - 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 TNFa in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFa expression. Furthermore, dexamethasone was synergistic or additive with E2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFa 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 (IRE1a) expression increased by E2. Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1a-mediated degradation of PI3K/Akt-associated signal pathways activated by E2. Unexpectedly, activated GR preferentially repressed nuclear factor-kB (NF-kB) DNA-binding activity and expression of NF-kB–dependent gene TNFa induced by E2, leading to the blockade of E2-induced apoptosis. Together, these data suggest that trans-suppression of NF-kB 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85072849490&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-18-1363
DO - 10.1158/1535-7163.MCT-18-1363
M3 - Article
C2 - 31511352
AN - SCOPUS:85072849490
SN - 1535-7163
VL - 18
SP - 1684
EP - 1695
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 10
ER -