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: Mitchell E Menezes, Xue-Ning Shen, Swadesh K Das, Luni Emdad, Chunqing Guo, Fang Yuan, You-Jun Li, Michael C Archer, Eldad Zacksenhaus, Jolene J Windle, Mark A Subler, Yaacov Ben-David, Devanand Sarkar, Xiang-Yang Wang, Paul B Fisher
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 36928-42 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26474456 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• interleukin-24
• Erbb2 protein, mouse
• Receptor, ErbB-2

Topics

• Animals
• Apoptosis
• Cell Differentiation
• Cell Transformation, Neoplastic (genetics)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Immunoenzyme Techniques
• Interleukins (physiology)
• Mammary Neoplasms, Animal (genetics, pathology)
• Mammary Tumor Virus, Mouse (genetics)
• Mice
• Mice, Transgenic
• Pregnancy
• Receptor, ErbB-2 (physiology)