Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment

Pharmacogenet Genomics. 2014 Sep;24(9):451-8. doi: 10.1097/FPC.0000000000000077.

Abstract

Objectives: Whereas paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. In addition, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor antagonism by mifepristone treatment in primary human cells have never been described.

Methods: As part of a randomized phase 1 clinical trial, we used microarrays to profile gene expression in peripheral blood cells sampled from each of four patients at baseline, after placebo/nanoparticle albumin-bound paclitaxel (nab-paclitaxel) treatment (cycle 1), and after mifepristone/nab-paclitaxel treatment (cycle 2).

Results: We found that 63 genes were differentially expressed following treatment with nab-paclitaxel, including multiple genes in the tubulin pathway. We also found 606 genes that were differentially expressed in response to mifepristone; genes downregulated by mifepristone overlapped significantly with those previously identified as being upregulated by dexamethasone.

Conclusion: These results provide insights into the mechanisms of paclitaxel and glucocorticoid receptor inhibition in peripheral blood cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / administration & dosage*
  • Albumins / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Dexamethasone / pharmacology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mifepristone / administration & dosage*
  • Mifepristone / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacology
  • Receptors, Glucocorticoid / antagonists & inhibitors*

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Receptors, Glucocorticoid
  • Mifepristone
  • Dexamethasone
  • Paclitaxel