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The antiprogestin Lonaprisan inhibits breast cancer cell proliferation by inducing p21 expression

L Busia1, H Faus, J Hoffmann

  • 1Bayer Schering Pharma AG, TRG Oncology, Berlin, Germany.

Molecular and Cellular Endocrinology
|December 9, 2010
PubMed

Insights

The novel antiprogestin Lonaprisan effectively inhibits breast cancer cell proliferation by inducing cell cycle arrest and a senescence-like state. This effect is mediated by the progesterone receptor (PR) and p21 induction, supporting antiprogestins as a potential breast cancer therapy.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Progesterone is crucial for mammary gland function and implicated in breast cancer development.
  • Antiprogestins, potent selective progesterone receptor (PR) antagonists, offer a potential therapeutic strategy for breast cancer.
  • Lonaprisan is a novel antiprogestin investigated for its effects on breast cancer cells.

Purpose of the Study:

  • To investigate the effects of the antiprogestin Lonaprisan on the T47D human breast cancer cell line.
  • To elucidate the molecular mechanisms underlying Lonaprisan's action, focusing on cell proliferation, cell cycle, and senescence.
  • To determine the role of the progesterone receptor (PR) and p21 in mediating Lonaprisan's effects.

Main Methods:

  • Treatment of T47D breast cancer cells with Lonaprisan.
  • Cell proliferation assays and cell cycle analysis (G0/G1 arrest).
  • Senescence-associated beta-galactosidase staining.
  • Western blot analysis for p21 and PR.
  • Chromatin immunoprecipitation (ChIP) assays to assess PR binding to the p21 promoter.
  • Site-directed mutagenesis of the PR DNA-binding domain.
  • Analysis of PR phosphorylation at Ser345 and interaction with c-Src.

Main Results:

  • Lonaprisan significantly inhibited T47D cell proliferation and induced G0/G1 cell cycle arrest.
  • A senescence-like phenotype was observed in Lonaprisan-treated cells.
  • Lonaprisan induced p21 expression via direct binding of the Lonaprisan-bound PR to the p21 promoter.
  • Intact PR DNA-binding activity was essential for p21 induction.
  • PR phosphorylation at Ser345 and interaction with c-Src were not required for p21 promoter activation.

Conclusions:

  • Lonaprisan demonstrates potent antiproliferative and senescence-inducing effects on breast cancer cells.
  • The mechanism involves PR-mediated transcriptional induction of p21, highlighting the importance of PR DNA-binding.
  • These findings support the therapeutic potential of antiprogestins like Lonaprisan in breast cancer treatment.
  • Further research is warranted to fully understand the therapeutic implications and mechanisms of antiprogestins in breast cancer.

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