Priority Research Papers:
MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer
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Abstract
Mitchell E. Menezes1, Xue-Ning Shen1, Swadesh K. Das1,2,3, Luni Emdad1,2,3, Chunqing Guo1, Fang Yuan1, You-Jun Li4, Michael C. Archer5,6, Eldad Zacksenhaus5,7, Jolene J. Windle1,2,3, Mark A. Subler1, Yaacov Ben-David5,8, Devanand Sarkar1,2,3, Xiang-Yang Wang1,2,3 and Paul B. Fisher1,2,3
1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
2 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
3 VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
4 Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China
5 Departments of Medical Biophysics, University of Toronto, Ontario, Canada
6 Nutritional Sciences, University of Toronto, Ontario, Canada
7 Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
8 Division of Biology, the Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China
Correspondence to:
Paul B. Fisher, email:
Keywords: melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), MMTV-PyMT mice, MMTV-MDA-7 mice, MMTV-MDA-7/MMTV-Erbb2 mice, transgenic mice
Received: July 06, 2015 Accepted: September 23, 2015 Published: October 12, 2015
Abstract
Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) is a novel member of the IL-10 gene family that selectively induces apoptosis and toxic autophagy in a broad spectrum of human cancers, including breast cancer, without harming normal cells or tissues. The ability to investigate the critical events underlying cancer initiation and progression, as well as the capacity to test the efficacy of novel therapeutics, has been significantly advanced by the development of genetically engineered mice (GEMs) that accurately recapitulate specific human cancers. We utilized three transgenic mouse models to better comprehend the in vivo role of MDA-7/IL-24 in breast cancer. Using the MMTV-PyMT spontaneous mammary tumor model, we confirmed that exogenously introducing MDA-7/IL-24 using a Cancer Terminator Virus caused a reduction in tumor burden and also produced an antitumor “bystander” effect. Next we performed xenograft studies in a newly created MMTV-MDA-7 transgenic model that over-expresses MDA-7/IL-24 in the mammary glands during pregnancy and lactation, and found that MDA-7/IL-24 overexpression delayed tumor growth following orthotopic injection of a murine PDX tumor cell line (mPDX) derived from a tumor formed in an MMTV-PyMT mouse. We also crossed the MMTV-MDA-7 line to MMTV-Erbb2 transgenic mice and found that MDA-7/IL-24 overexpression delayed the onset of mammary tumor development in this model of spontaneous mammary tumorigenesis as well. Finally, we assessed the role of MDA-7/IL-24 in immune regulation, which can potentially contribute to tumor suppression in vivo. Our findings provide further direct in vivo evidence for the role of MDA-7/IL-24 in tumor suppression in breast cancer in immune-competent transgenic mice.
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