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Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer

M Razandi1, A Pedram, V C Jordan

  • 1Division of Endocrinology, Medical Service 111-I, Veterans Affairs Medical Center, Long Beach, CA, USA.

Oncogene
|August 22, 2012
PubMed

Insights

Tamoxifen resistance in breast cancer involves mitochondrial estrogen receptor beta (ERβ) and manganese superoxide dismutase (MnSOD). Targeting these can restore tamoxifen

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Tamoxifen (TAM) is a crucial breast cancer therapy with cytostatic and cytotoxic effects.
  • Mitochondrial estrogen receptor beta (ERβ) plays a role in TAM's mechanism of action.
  • Reactive oxygen species (ROS) are implicated in TAM-induced cancer cell death.

Purpose of the Study:

  • To investigate the role of mitochondrial ERβ and manganese superoxide dismutase (MnSOD) in TAM resistance.
  • To elucidate the mechanisms by which TAM modulates ROS and induces apoptosis.
  • To identify potential therapeutic targets for overcoming TAM resistance.

Main Methods:

  • Utilized MCF7-BK and MCF7-BK-TR cell lines to study TAM effects.
  • Assessed mitochondrial ERβ activity, ROS production, and MnSOD levels.
  • Employed lentiviral shRNA to knock down MnSOD in mouse xenograft models.

Main Results:

  • TAM acted as an antagonist of mitochondrial ERβ in MCF7-BK cells, increasing ROS and cytotoxicity.
  • TAM-induced cytotoxicity was linked to MnSOD downregulation via tyrosine 34 nitrosylation, leading to ROS generation and apoptosis.
  • In MCF7-BK-TR cells, agonistic effects on mitochondrial ERβ stimulated MnSOD, preventing ROS increase and cell death.
  • Knockdown of MnSOD in mouse xenografts sensitized tumors to TAM, inducing apoptosis.

Conclusions:

  • Mitochondrial ERβ and MnSOD activity are critical determinants of TAM sensitivity and resistance in breast cancer.
  • TAM resistance can be reversed by targeting tumor MnSOD and mitochondrial ERβ to enhance cell death.
  • These findings highlight novel therapeutic strategies for improving breast cancer treatment outcomes.

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