Chemotherapy agents like paclitaxel are often a first line of therapy for triple-negative breast cancer patients and a last line of therapy for other aggressive breast cancers. While such agents are effective pro-apoptotic treatments for breast cancer cells, they produce many unwanted side effects. Synthetic glucocorticoids like dexamethasone are commonly prescribed during chemotherapy treatment of breast cancer patients for anti-emetic and anti-hypersensitivity purposes. Dexamethasone, however, is known to enhance cell survival in solid tumors. The prevalent use of dexamethasone in conjunction with paclitaxel in the treatment of breast cancer patients merits concern. Previous studies demonstrate dexamethasone-mediated survival in a subset of breast cancer cells in the presence of paclitaxel. This work expanded the types of cell lines studied and explored the molecular mechanism driving this phenotype. Human breast cancer cell lines representative of several subtypes of breast cancer including triple-negative breast cancer, luminal, and HER2 were treated in the presence and absence of paclitaxel, dexamethasone, and under co-treatment conditions. Cell survival was monitored under differing conditions. We then manipulated aspects of the nuclear factor kappa B (NFkappaB) signaling pathway to elucidate the importance of this pathway in overcoming chemotherapy treatment. All cell lines tested were sensitive to paclitaxel and showed dexamethasone-mediated rescue from paclitaxel-induced apoptosis, but the rescue of overall cell numbers was most pronounced in triple-negative breast cancer cell lines. Dexamethasone and paclitaxel inversely regulated the activity of NFkappaB, which is essential to both paclitaxel-mediated apoptosis and dexamethasone-mediated rescue. The transcriptional target of NFkappaB, Fas receptor, is inversely regulated by paclitaxel and dexamethasone and is a downstream target of paclitaxel-activated NFkappaB. Dexamethasone antagonizes paclitaxel-mediated apoptosis through inhibition of NFkappaB transcription of Fas receptor. Pre-treatment of breast cancer patients with dexamethasone may greatly reduce patient response to paclitaxel. Our study elucidates a novel mechanism of paclitaxel-induced apoptosis in breast cancer cell lines and explicates dexamethasone’s antagonism of paclitaxel.
NFκB Apoptosis Chemotherapy Breast cancer Steroids
Nuclear factor kappa B
Triple-negative breast cancers
Dulbecco’s Modified Eagle’s Medium
This is a preview of subscription content, log in to check access.
Sincere thanks to Tiffany Seagroves and Christine Pratt for cell lines and expression constructs. We are grateful to Elizabeth Fidalgo da Silva, Jiamila Maimaiti, and Espanta Jalili for technical support. We thank Suzanne Conzen for valuable discussions and the Breast Cancer Society of Canada and Natural Science and Engineering Research Council of Canada for equipment support. This work was funded by Windsor Essex Country Cancer Centre Foundation’s Seeds4Hope program.
Compliance with ethical standards
Conflict of interest
The authors have no competing interests to declare.
Berger SA, Cole TJ, Schmid W, Schutz G (1996) Molecular genetic analysis of glucocorticoid and mineralocorticoid signaling in development and physiological processes. Steroids 61(4):236–239CrossRefPubMedGoogle Scholar
Wintermantel TM, Bock D, Fleig V, Greiner EF, Schutz G (2005) The epithelial glucocorticoid receptor is required for the normal timing of cell proliferation during mammary lobuloalveolar development but is dispensable for milk production. Mol Endocrinol 19(2):340–349CrossRefPubMedGoogle Scholar
Distelhorst CW (2002) Recent insights into the mechanism of glucocorticosteroid-induced apoptosis. Cell Death Differ 9(1):6–19CrossRefPubMedGoogle Scholar
Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, Conzen SD (2004) Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Res 64(5):1757–1764CrossRefPubMedGoogle Scholar
Frankfurt O, Rosen ST (2004) Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 16(6):553–563CrossRefPubMedGoogle Scholar
Sui M, Chen F, Chen Z, Fan W (2006) Glucocorticoids interfere with therapeutic efficacy of paclitaxel against human breast and ovarian xenograft tumors. Int J Cancer 119(3):712–717CrossRefPubMedGoogle Scholar
Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD (2001) Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem 276(20):16649–16654CrossRefPubMedGoogle Scholar
Pang D, Kocherginsky M, Krausz T, Kim SY, Conzen SD (2006) Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis. Cancer Biol Ther 5(8):933–940CrossRefPubMedGoogle Scholar
Skor MN, Wonder EL, Kocherginsky M, Goyal A, Hall BA, Cai Y, Conzen SD (2013) Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clin Cancer Res 19(22):6163–6172CrossRefPubMedGoogle Scholar
Torres K, Horwitz SB (1998) Mechanisms of Taxol-induced cell death are concentration dependent. Cancer Res 58(16):3620–3626PubMedGoogle Scholar
Wu W, Pew T, Zou M, Pang D, Conzen SD (2005) Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival. J Biol Chem 280(6):4117–4124CrossRefPubMedGoogle Scholar
Wu W, Zou M, Brickley DR, Pew T, Conzen SD (2006) Glucocorticoid receptor activation signals through forkhead transcription factor 3a in breast cancer cells. Mol Endocrinol 20(10):2304–2314CrossRefPubMedGoogle Scholar
Huang Y, Fang Y, Dziadyk JM, Norris JS, Fan W (2002) The possible correlation between activation of NF-kappaB/IkappaB pathway and the susceptibility of tumor cells to paclitaxel-induced apoptosis. Oncol Res 13(2):113–122PubMedGoogle Scholar
Huang Y, Johnson KR, Norris JS, Fan W (2000) Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells. Cancer Res 60(16):4426–4432PubMedGoogle Scholar
Huang Y, Fan W (2002) IkappaB kinase activation is involved in regulation of paclitaxel-induced apoptosis in human tumor cell lines. Mol Pharmacol 61(1):105–113CrossRefPubMedGoogle Scholar
Chan H, Bartos DP, Owen-Schaub LB (1999) Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50-p65 recruitment. Mol Cell Biol 19(3):2098–2108PubMedCentralPubMedGoogle Scholar
Matsui K, Fine A, Zhu B, Marshak-Rothstein A, Ju ST (1998) Identification of two NF-kappa B sites in mouse CD95 ligand (Fas ligand) promoter: functional analysis in T cell hybridoma. J Immunol 161(7):3469–3473PubMedGoogle Scholar
Moos PJ, Fitzpatrick FA (1998) Taxane-mediated gene induction is independent of microtubule stabilization: induction of transcription regulators and enzymes that modulate inflammation and apoptosis. Proc Natl Acad Sci USA 95(7):3896–3901PubMedCentralCrossRefPubMedGoogle Scholar
Uozumi J, Koikawa Y, Yasumasu T, Tokuda N, Kumazawa J (1996) The protective effect of methylprednisolone against cisplatin-induced nephrotoxicity in patients with urothelial tumors. Int J Urol 3(5):343–347CrossRefPubMedGoogle Scholar
Herr I, Ucur E, Herzer K, Okouoyo S, Ridder R, Krammer PH, von Knebel Doeberitz M, Debatin KM (2003) Glucocorticoid cotreatment induces apoptosis resistance toward cancer therapy in carcinomas. Cancer Res 63(12):3112–3120PubMedGoogle Scholar