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Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer.

Publication ,  Journal Article
Huang, Y; Hu, W; Huang, J; Shen, F; Sun, Y; Ivan, C; Pradeep, S; Dood, R; Haemmerle, M; Jiang, D; Mangala, LS; Noh, K; Hansen, JM; Sood, AK ...
Published in: Mol Cancer Ther
February 2018

Although progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464-73. ©2017 AACR.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

February 2018

Volume

17

Issue

2

Start / End Page

464 / 473

Location

United States

Related Subject Headings

  • Uterine Neoplasms
  • Receptors, Progesterone
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice
  • Humans
  • Gonanes
  • Female
  • Cell Line, Tumor
  • Antineoplastic Agents
 

Citation

APA
Chicago
ICMJE
MLA
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Huang, Y., Hu, W., Huang, J., Shen, F., Sun, Y., Ivan, C., … Sood, A. K. (2018). Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer. Mol Cancer Ther, 17(2), 464–473. https://doi.org/10.1158/1535-7163.MCT-17-0006
Huang, Yan, Wei Hu, Jie Huang, Fangrong Shen, Yunjie Sun, Cristina Ivan, Sunila Pradeep, et al. “Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer.Mol Cancer Ther 17, no. 2 (February 2018): 464–73. https://doi.org/10.1158/1535-7163.MCT-17-0006.
Huang Y, Hu W, Huang J, Shen F, Sun Y, Ivan C, et al. Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer. Mol Cancer Ther. 2018 Feb;17(2):464–73.
Huang, Yan, et al. “Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer.Mol Cancer Ther, vol. 17, no. 2, Feb. 2018, pp. 464–73. Pubmed, doi:10.1158/1535-7163.MCT-17-0006.
Huang Y, Hu W, Huang J, Shen F, Sun Y, Ivan C, Pradeep S, Dood R, Haemmerle M, Jiang D, Mangala LS, Noh K, Hansen JM, Dalton HJ, Previs RA, Nagaraja AS, McGuire M, Jennings NB, Broaddus R, Coleman RL, Sood AK. Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer. Mol Cancer Ther. 2018 Feb;17(2):464–473.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

February 2018

Volume

17

Issue

2

Start / End Page

464 / 473

Location

United States

Related Subject Headings

  • Uterine Neoplasms
  • Receptors, Progesterone
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice
  • Humans
  • Gonanes
  • Female
  • Cell Line, Tumor
  • Antineoplastic Agents