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Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer.

Publication ,  Journal Article
Kobayashi, S; Stice, JP; Kazmin, D; Wittmann, BM; Kimbrel, EA; Edwards, DP; Chang, C-Y; McDonnell, DP
Published in: Mol Endocrinol
December 2010

Both pro- and antimitogenic activities have been ascribed to progesterone receptor (PR) agonists and antagonists in breast cancer cells; however, the transcriptional responses that underlie these paradoxical functions are not apparent. Using nontransformed, normal human mammary epithelial cells engineered to express PR and standard microarray technology, we defined 2370 genes that were significantly regulated by the PR agonist R5020. Gene ontology (GO) analysis revealed that GO terms involved in inflammation and nuclear factor-κB (NF-κB) signaling were among the most significantly regulated. Interestingly, on those NF-κB responsive genes that were inhibited by agonist-activated PR, antagonists either 1) mimicked the actions of agonists or 2) reversed the inhibitory actions of agonists. This difference in pharmacological response could be attributed to the fact that although agonist- and antagonist-activated PR is recruited to NF-κB-responsive promoters, the physical presence of PR tethered to the promoter of some genes is sufficient for transcriptional inhibition, whereas on others, an agonist-activated PR conformation is required for inhibition of NF-κB signaling. Importantly, the actions of PR on the latter class of genes were reversed by an activation function-2-inhibiting, LXXLL-containing peptide. Consideration of the relative activities of these distinct antiinflammatory pathways in breast cancer may be instructive with respect to the likely therapeutic activity of PR agonists or antagonists in the treatment of breast cancer.

Duke Scholars

Published In

Mol Endocrinol

DOI

EISSN

1944-9917

Publication Date

December 2010

Volume

24

Issue

12

Start / End Page

2292 / 2302

Location

United States

Related Subject Headings

  • Translocation, Genetic
  • Transcriptional Activation
  • Signal Transduction
  • Receptors, Progesterone
  • RNA, Messenger
  • Protein Isoforms
  • Promoter Regions, Genetic
  • Progestins
  • Progesterone
  • NF-kappa B
 

Citation

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Kobayashi, S., Stice, J. P., Kazmin, D., Wittmann, B. M., Kimbrel, E. A., Edwards, D. P., … McDonnell, D. P. (2010). Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer. Mol Endocrinol, 24(12), 2292–2302. https://doi.org/10.1210/me.2010-0289
Kobayashi, Sakiko, James P. Stice, Dmitri Kazmin, Bryan M. Wittmann, Erin A. Kimbrel, Dean P. Edwards, Ching-Yi Chang, and Donald P. McDonnell. “Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer.Mol Endocrinol 24, no. 12 (December 2010): 2292–2302. https://doi.org/10.1210/me.2010-0289.
Kobayashi S, Stice JP, Kazmin D, Wittmann BM, Kimbrel EA, Edwards DP, et al. Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer. Mol Endocrinol. 2010 Dec;24(12):2292–302.
Kobayashi, Sakiko, et al. “Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer.Mol Endocrinol, vol. 24, no. 12, Dec. 2010, pp. 2292–302. Pubmed, doi:10.1210/me.2010-0289.
Kobayashi S, Stice JP, Kazmin D, Wittmann BM, Kimbrel EA, Edwards DP, Chang C-Y, McDonnell DP. Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer. Mol Endocrinol. 2010 Dec;24(12):2292–2302.

Published In

Mol Endocrinol

DOI

EISSN

1944-9917

Publication Date

December 2010

Volume

24

Issue

12

Start / End Page

2292 / 2302

Location

United States

Related Subject Headings

  • Translocation, Genetic
  • Transcriptional Activation
  • Signal Transduction
  • Receptors, Progesterone
  • RNA, Messenger
  • Protein Isoforms
  • Promoter Regions, Genetic
  • Progestins
  • Progesterone
  • NF-kappa B