Aim: Whereas earlier reports highlighted a tumor suppressor role for MnSOD, recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present report, 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 apoptosis, while drug resistance was associated with increased MnSOD expression. In an attempt to develop a clinically relevant approach to downregulate MnSOD expression in patient 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 PPAR 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 expressions. 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 downregulating MnSOD to increase the chemosensitivity of this subtype of breast carcinoma.
Alan Prem Kumar1,2,7,16,*, Ser Yue Loo1,3,*, Sung Won Shin8, Tuan Zea Tan1, Chon Boon Eng9, Rajeev Singh4,9, Thomas Choudary Putti5, Chee Wee Ong1,10, Manuel Salto-Tellez1,5,10, Boon Cher Goh1,11, Joo In Park8, Jean Paul Thiery1,3,12, Shazib Pervaiz1,6,13,14,15,§, Marie Veronique Clement3,13,#,§
* These authors contributed equally to this work § Contributed equally to senior authorship
1Cancer Science Institute of Singapore, National University of Singapore; Departments of 2Pharmacology, 3Biochemistry, 4Surgery, 5Pathology, and 6Physiology, Yong Loo Lin School of Medicine, National University of Singapore
7School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia; 8Department of Biochemistry, Dong-A University College of Medicine and Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan, South Korea;
9NUH-NUS Tissue Repository, National University Hospital, Singapore;
10Centre for Cancer Research and Cell Biology, Queen’s University Belfast, United Kingdom; 11Department of Haematology-Oncology, National University Hospital, Singapore
12Institute of Molecular and Cellular Biology, A*Star Singapore
13NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore
14Duke-NUS Graduate Medical School, Singapore
16epartment of Biological Sciences, University of North Texas, Denton, Texas, United States.