Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer

Breast Cancer Res. 2012 Jul 19;14(4):R108. doi: 10.1186/bcr3229.


Introduction: The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models.

Methods: Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells.

Results: Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment.

Conclusion: Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.

Publication types

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

MeSH terms

  • Animals
  • Benzamides / administration & dosage
  • Benzamides / pharmacology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Carcinogens
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Co-Repressor Proteins / genetics*
  • Co-Repressor Proteins / metabolism
  • Cyclopropanes / administration & dosage
  • Cyclopropanes / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Epigenesis, Genetic
  • Estrogens / pharmacology
  • Female
  • Gene Knockdown Techniques
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / metabolism*
  • Histones / metabolism
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Pargyline / pharmacology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • 2-(3-(3-benzamido-4-(benzylamino)-4-oxobutoxy)phenyl)cyclopropylamine
  • Benzamides
  • Carcinogens
  • Co-Repressor Proteins
  • Cyclopropanes
  • Estrogens
  • Histones
  • PELP1 protein, human
  • Transcription Factors
  • Pargyline
  • Histone Demethylases
  • KDM1A protein, human