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Mechanism of inhibition of MMTV-neu and MMTV-wnt1 induced mammary oncogenesis by RARα agonist AM580

Oncogene volume 29, pages 3665–3676 (2010)Cite this article

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Abstract

We hypothesized that specific activation of a single retinoic acid receptor-α (RARα), without direct and concurrent activation of RARβ and γ, will inhibit mammary tumor oncogenesis in murine models relevant to human cancer. A total of 50 uniparous mouse mammary tumor virus (MMTV)-neu and 50 nuliparous MMTV-wnt1 transgenic mice were treated with RARα agonist (retinobenzoic acid, Am580) that was added to the diet for 40 (neu) and 35 weeks (wnt1), respectively. Among the shared antitumor effects was the inhibition of epithelial hyperplasia, a significant increase (P<0.05) in tumor-free survival and a reduction in tumor incidence and in the growth of established tumors. In both models, the mechanisms responsible for these effects involved inhibition of proliferation and survival pathways, and induction of apoptosis. The treatment was more effective in the MMTV-wnt1 model in which Am580 also induced differentiation, in both in vivo and three-dimensional (3D) cultures. In these tumors Am580 inhibited the wnt pathway, measured by loss of nuclear β-catenin, suggesting partial oncogene dependence of therapy. Am580 treatment increased RARβ and lowered the level of RARγ, an isotype whose expression we linked with tumor proliferation. The anticancer effect of RARα, together with the newly discovered pro-proliferative role of RARγ, suggests that specific activation of RARα and inhibition of RARγ might be effective in breast cancer therapy.

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Acknowledgements

We thank Drs W Muller and HE Varmus, respectively, for the gift of MMTV-neu and MMTV-wnt1 mice, Dr K Shudo for generous gift of AM580 in amounts sufficient to complete these extensive in vivo studies, and Drs L Ossowski, S Waxman and J Aguirre-Ghiso for helpful advice. This work was supported by the NCI Grant R01-CA119018, the Samuel Waxman Cancer Research Foundation (SWCRF) and the NIH-NCI shared resources Grant 5R24-CA095823-04, NSF Major Research Instrumentation Grant DBI-972404, the NIH shared instrumentation Grant 1S10-RR0-9145-01 to MSSM's Microscopy Shared Resources Facility.

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  1. Division of Hematology-Oncology, Department of Medicine, Tisch Cancer Center, Mount Sinai School of Medicine, New York, NY, USA

    Y Lu, S Bertran, T-A Samuels, R Mira-y-Lopez & E F Farias

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Correspondence to E F Farias.

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Lu, Y., Bertran, S., Samuels, TA. et al. Mechanism of inhibition of MMTV-neu and MMTV-wnt1 induced mammary oncogenesis by RARα agonist AM580. Oncogene 29, 3665–3676 (2010). https://doi.org/10.1038/onc.2010.119

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