title: MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer.
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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Departments of Medical Biophysics, University of Toronto, Ontario, Canada.|Nutritional Sciences, University of Toronto, Ontario, Canada.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Archer
authors.affiliation: Departments of Medical Biophysics, University of Toronto, Ontario, Canada.|Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Departments of Medical Biophysics, University of Toronto, Ontario, Canada.|Division of Biology, the Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D007378:Interleukins / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000099180:Interleukin-24; C524056:Erbb2 protein, mouse
keywords: MMTV-MDA-7 mice; MMTV-MDA-7/MMTV-Erbb2 mice; MMTV-PyMT mice; melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24); transgenic mice