Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype

Xianghui Zou, Cesar Augusto Santa-Maria, Joseph O'Brien, David Gius, Yueming Zhu*

*Corresponding author for this work

Research output: Contribution to journalReview article

22 Scopus citations

Abstract

Significance: Breast cancer is the most common nondermatologic malignancy among women in the United States, among which endocrine receptor-positive breast cancer accounts for up to 80%. Endocrine receptor-positive breast cancers can be categorized molecularly into luminal A and B subtypes, of which the latter is an aggressive form that is less responsive to endocrine therapy with inferior prognosis. Recent Advances: Sirtuin, an aging-related gene involved in mitochondrial metabolism, is associated with life span, and more importantly, murine models lacking Sirt3 spontaneously develop tumors that resemble human luminal B breast cancer. Furthermore, these tumors exhibit aberrant manganese superoxide dismutase (MnSOD) acetylation at lysine 68 and lysine 122 and have abnormally high reactive oxygen species (ROS) levels, which have been observed in many types of breast cancer. Critical Issues: The mechanism of how luminal B breast cancer develops resistance to endocrine therapy remains unclear. MnSOD, a primary mitochondrial detoxification enzyme, functions by scavenging excessive ROS from the mitochondria and maintaining mitochondrial and cellular homeostasis. Sirt3, a mitochondrial fidelity protein, can regulate the activity of MnSOD through deacetylation. In this study, we discuss a possible mechanism of how loss of SIRT3-guided MnSOD acetylation results in endocrine therapy resistance of human luminal B breast cancer. Future Directions: Acetylation of MnSOD and other mitochondrial proteins, due to loss of SIRT3, may explain the connection between ROS and development of luminal B breast cancer and how luminal B breast cancer becomes resistant to endocrine therapy. Antioxid. Redox Signal. 25, 326-336.

Original languageEnglish (US)
Pages (from-to)326-336
Number of pages11
JournalAntioxidants and Redox Signaling
Volume25
Issue number6
DOIs
StatePublished - Aug 20 2016

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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