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Suppression of Her2/Neu mammary tumor development in mda-7/IL-24 transgenic mice
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You-Jun Li1,*, Guodong Liu2,*, Lei Xia4, Xiao Xiao4, Jeff C. Liu5, Mitchell E. Menezes6, Swadesh K. Das6, Luni Emdad6, Devanand Sarkar6, Paul B. Fisher6, Michael C. Archer2,3, Eldad Zacksenhaus3,5 and Yaacov Ben-David3,4
1 Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China
2 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
4 Division of Biology, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China
5 Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
6 Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
* These authors have contributed equally to this work
Yaacov Ben-David, email:
Eldad Zacksenhaus, email:
Keywords: mda-7/IL-24, HER2, breast cancer, prevention, mouse model
Received: July 06, 2015 Accepted: September 23, 2015 Published: October 09, 2015
Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) encodes a tumor suppressor gene implicated in the growth of various tumor types including breast cancer. We previously demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of carcinogen-treated (methylnitrosourea, MNU) rats suppressed mammary tumor development. Since most MNU-induced tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu-induced mammary tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with doxycycline exhibited a strong inhibition of tumor development, demonstrating tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of tumors generated following injection of Her2/Neu tumor cells isolated from triple compound transgenic mice that had not been treated with doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression, tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this cytokine within tumor microenvironment is crucial to sustain tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its tumor suppression effect on HER2+ breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary tumor development and provide a rationale for using this cytokine in the prevention/treatment of human breast cancer.
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