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TARGETING THE GENOTOXIC EFFECTS OF ESTROGENS

Monica M Montano1, Nirmala Krishnamurthy, Smitha Sripathy

  • 1Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106.

Drug Discovery Today. Disease Mechanisms
|June 25, 2013
PubMed

Insights

Selective Estrogen Receptor Modulators (SERMs) boost protective antioxidant enzymes in breast cells via Estrogen Receptor beta (ERβ) and hPMC2, preventing DNA damage and tumors. This involves hPMC2

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endocrinology

Background:

  • Estrogen signaling is implicated in breast epithelial cell proliferation and mammary tumorigenesis.
  • Selective Estrogen Receptor Modulators (SERMs) are used in breast cancer treatment and prevention.
  • Oxidative stress and DNA damage are key factors in estrogen-induced cancer development.

Purpose of the Study:

  • To investigate the role of SERMs in upregulating antioxidative stress enzymes in breast epithelial cells.
  • To identify the molecular mechanisms and key proteins involved in SERM-mediated protection against estrogen genotoxicity.
  • To elucidate the function of the human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2) in this pathway.

Main Methods:

  • Utilized breast epithelial cell lines for in vitro studies.
  • Assessed the expression levels of antioxidative stress enzymes.
  • Investigated the requirement of Estrogen Receptor beta (ERβ) and hPMC2 for SERM effects.
  • Examined the functional exonuclease domain of hPMC2.

Main Results:

  • SERMs upregulate antioxidative stress enzymes in breast epithelial cells.
  • This upregulation is dependent on both ERβ and hPMC2.
  • hPMC2 possesses a functional exonuclease domain essential for this process.
  • hPMC2's exonuclease activity is required for repairing estrogen-induced abasic sites.

Conclusions:

  • SERMs confer protection against estrogen's genotoxic effects and mammary tumorigenesis through ERβ and hPMC2.
  • hPMC2 plays a critical role in upregulating antioxidative stress enzymes and repairing DNA damage induced by estrogens.
  • The findings highlight a novel mechanism of chemoprevention involving ERβ, hPMC2, and antioxidative pathways.

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