Estrogen-dependent regulation of Eg5 in breast cancer cells

Maricarmen D. Planas-Silva, Irina S. Filatova

Research output: Contribution to journalArticlepeer-review

Abstract

HsEg5 (Eg5) is a kinesin required for proper execution of mitosis. Several compounds that specifically block Eg5 are in clinical development and have the potential to be used in the treatment of breast cancer. In this study, we investigated the interaction between Eg5 and estrogen receptor signaling. We observed decreased Eg5 expression after treatment of estrogen receptor-positive human breast cancer MCF-7 cells with the estrogen receptor downregulator fulvestrant. Downregulation of Eg5 expression in response to fulvestrant was also observed in another estrogen receptor-positive cell line ZR-75, but not in the estrogen receptor-negative breast cancer cell line MDA-231. Moreover, in MCF-7 cells previously arrested in the G0/G1 phase of the cell cycle by fulvestrant, addition of estrogen increased Eg5 expression. This upregulation correlated with progression through S-phase. Nevertheless, the effect of fulvestrant in Eg5 expression could not be explained solely by cell cycle arrest, because treatments that blocked cell cycle progression did not consistently decrease Eg5 expression. Pharmacological inhibition of Eg5 function, with either S-trityl-L-cysteine or monastrol, prevented growth of estrogen-treated MCF-7 cells with an IC50 of 0.46 and 29.71 μmol/l, respectively. Simultaneous inhibition of estrogen receptor function with fulvestrant increased the IC50 for S-trityl-L-cysteine to 2.30 μmol/l and for monastrol to 112.69 μmol/l. Our results suggest that pharmacological inhibition of Eg5 may be an effective treatment for estrogen receptor-positive breast cancer, even without concomitant hormonal therapy.

Original languageEnglish (US)
Pages (from-to)773-779
Number of pages7
JournalAnti-cancer drugs
Volume18
Issue number7
DOIs
StatePublished - Aug 1 2007

Keywords

  • Breast cancer
  • Cell cycle
  • Eg5
  • Estrogen receptor
  • Kinesin

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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