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Breast Cancer Research and Treatment

, Volume 154, Issue 1, pp 33–44 | Cite as

Paclitaxel-induced transcriptional regulation of Fas signaling pathway is antagonized by dexamethasone

  • Martin Crozier
  • Lisa A. Porter
Preclinical Study

Abstract

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.

Keywords

NFκB Apoptosis Chemotherapy Breast cancer Steroids 

Abbreviations

GCs

Glucocorticoids

GR

Glucocorticoid receptor

Dex

Dexamethasone

Pac

Paclitaxel

NFκB

Nuclear factor kappa B

TNBCs

Triple-negative breast cancers

FASLG

Fas ligand

FAS

Fas receptor

DMEM

Dulbecco’s Modified Eagle’s Medium

RU-486

Mifepristone

μM

Micro-molar

h

Hour

Notes

Acknowledgments

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.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of WindsorWindsorCanada

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