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Published on: May 18, 2020
Suppression of Her2/Neu mammary tumor development in mda-7/IL-24 transgenic mice
You-Jun Li1, Guodong Liu2, Lei Xia3
1Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China.
Abstract:
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.
Insights
Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) suppresses Her2/Neu-induced mammary tumors in mice. Continuous expression is crucial for sustained tumor inhibition, suggesting its potential for breast cancer prevention and treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a tumor suppressor gene involved in various cancers.
- Previous studies showed mda-7/IL-24 suppresses mammary tumor development in rats.
- Human breast cancers often differ in genetic mutations from carcinogen-induced rat models.
Purpose of the Study:
- To investigate the tumor suppressor activity of mda-7/IL-24 in Her2/Neu-induced mammary tumors.
- To evaluate the efficacy of inducible mda-7/IL-24 expression in a relevant mouse model.
- To understand the mechanism of mda-7/IL-24-mediated tumor suppression in breast cancer.
Main Methods:
- Generation of tet-inducible mda-7/IL-24 transgenic mice crossed with Her2/Neu transgenic mice.
- Administration of doxycycline to induce mda-7/IL-24 expression and assess tumor development.
- Xenotransplantation of Her2/Neu tumor cells into isogenic mice to evaluate mda-7/IL-24 effects.
- Analysis of mda-7/IL-24 expression dynamics and its correlation with tumor growth.
- Investigation of downstream effectors, including PERP, involved in mda-7/IL-24's mechanism.
Main Results:
- Doxycycline-induced mda-7/IL-24 expression strongly inhibited Her2/Neu-induced mammary tumor development in transgenic mice.
- mda-7/IL-24 induction suppressed the growth of established Her2/Neu tumors upon xenotransplantation.
- Tumorigenesis resumed upon loss of mda-7/IL-24 expression, highlighting the need for continuous cytokine presence.
- MDA-7/IL-24's tumor suppressive effects on HER2+ breast cancer cells involved PERP, a growth arrest and apoptosis inducer.
Conclusions:
- mda-7/IL-24 demonstrates significant tumor suppressor activity against Her2/Neu-induced mammary tumors in immune-competent mice.
- Sustained expression of mda-7/IL-24 within the tumor microenvironment is critical for maintaining its inhibitory effects.
- These findings support the therapeutic potential of mda-7/IL-24 for the prevention and treatment of human breast cancer, particularly HER2+ subtypes.
