Manganese Superoxide Dismutase Is a Promising Target for Enhancing Chemosensitivity of Basal-Like Breast Carcinoma

Alan Prem Kumar, Ser Yue Loo, Sung Won Shin, Tuan Zea Tan, Chon Boon Eng, Rajeev Singh, Thomas Choudary Putti, Chee Wee Ong, Manuel Salto-Tellez, Boon Cher Goh, Joo In Park, Jean Paul Thiery, Shazib Pervaiz, Marie Veronique Clement

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

AIMS: Although earlier reports highlighted a tumor suppressor role for manganese superoxide dismutase (MnSOD), recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present article, we hypothesized that MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype, and targeting MnSOD could be an attractive strategy for enhancing chemosensitivity of this highly aggressive breast cancer subtype.

RESULTS: Using MDA-MB-231 and BT549 as a model of basal breast cancer cell lines, we show that knockdown of MnSOD decreased the colony-forming ability and sensitized the cells to drug-induced cell death, while drug resistance was associated with increased MnSOD expression. In an attempt to develop a clinically relevant approach to down-regulate MnSOD expression in patients with basal breast carcinoma, we employed activation of the peroxisome proliferator-activated receptor gamma (PPARγ) to repress MnSOD expression; PPARγ activation significantly reduced MnSOD expression, increased chemosensitivity, and inhibited tumor growth. Moreover, as a proof of concept for the clinical use of PPARγ agonists to decrease MnSOD expression, biopsies derived from breast cancer patients who had received synthetic PPARγ ligands as anti-diabetic therapy had significantly reduced MnSOD expression. Finally, we provide evidence to implicate peroxynitrite as the mechanism involved in the increased sensitivity to chemotherapy induced by MnSOD repression.

INNOVATION AND CONCLUSION: These data provide evidence to link increased MnSOD expression with the aggressive basal breast cancer, and underscore the judicious use of PPARγ ligands for specifically down-regulating MnSOD to increase the chemosensitivity of this subtype of breast carcinoma.

Original languageEnglish
Pages (from-to)2326-2346
Number of pages21
JournalAntioxidants & Redox Signaling
Volume20
Issue number15
Early online date14 Nov 2013
DOIs
Publication statusPublished - 30 Apr 2014

Keywords

  • Animals
  • Antineoplastic Agents
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Survival
  • Claudins
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Ligands
  • Mice
  • Mitochondria
  • Neoplasms, Basal Cell
  • Nitric Oxide
  • PPAR gamma
  • Peroxynitrous Acid
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

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  • Cite this

    Kumar, A. P., Loo, S. Y., Shin, S. W., Tan, T. Z., Eng, C. B., Singh, R., Putti, T. C., Ong, C. W., Salto-Tellez, M., Goh, B. C., Park, J. I., Thiery, J. P., Pervaiz, S., & Clement, M. V. (2014). Manganese Superoxide Dismutase Is a Promising Target for Enhancing Chemosensitivity of Basal-Like Breast Carcinoma. Antioxidants & Redox Signaling, 20(15), 2326-2346. https://doi.org/10.1089/ars.2013.5295