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

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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 (Pin 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.