Progesterone receptor antagonism inhibits progestogen-related carcinogenesis and suppresses tumor cell proliferation

Oukseub Lee, Mi Ran Choi, Konstantin Christov, David Ivancic, Seema A. Khan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Purpose: Blockade of the progestogen-progesterone receptor (PR) axis is a novel but untested strategy for breast cancer prevention. We report preclinical data evaluating telapristone acetate (TPA), ulipristal acetate (UPA), and mifepristone. Methods: Tumors were induced with medroxyprogesterone acetate (MPA) plus 7,12-dimethylbenz[a]anthracene (DMBA) in mice, and MPA or progesterone plus N-methyl-N-nitrosourea (MNU) in rats. Mammary gland histology, tumor incidence, latency, multiplicity, burden and histology were evaluated, along with immunohistochemical labeling of pHH3 (proliferation), CD34 (angiogenesis), and estrogen and progesterone receptors (ER and PR). A concentration gradient of TPA, UPA, and mifepristone was tested for growth inhibition of T47D spheroids. Results: In mouse mammary glands, no tumors formed, but TPA opposed the pro-hyperplastic effects of MPA (p = 0.002). In rats, TPA decreased tumor incidence (p = 0.037 for MPA + TPA vs. MPA, and p = 0.032 for progesterone + TPA vs. progesterone) and tumor burden (p = 0.042 for progesterone + TPA vs. progesterone), with significant decreases in pHH3 and CD34 positive cells. TPA and UPA were superior to mifepristone in growth inhibition of T47D spheroids. Conclusion: TPA has consistent anti-tumorigenic effects in several models, which are accompanied by decreases in cell proliferation, angiogenesis, and hormone receptor expression.

Original languageEnglish (US)
Pages (from-to)310-317
Number of pages8
JournalCancer Letters
Volume376
Issue number2
DOIs
StatePublished - Jul 1 2016

Keywords

  • Mammary carcinogenesis
  • Prevention
  • Progesterone receptor
  • Progestogen
  • Rats
  • Telapristone acetate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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