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

Abstract

We hypothesized that specific activation of a single retinoic acid receptor, RARα without direct and concurrent activation of RARβ and γ, will inhibit mammary tumor oncogenesis in murine models relevant to human cancer. Fifty uniparous MMTV-neu and 50 nuliparous MMTV-wnt1 transgenic mice were treated with RARα agonist, (retinobenzoic acid, Am580) added to the diet for 40 (neu) and 35 weeks (wnt1), respectively. Among the shared anti-tumor 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 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, both in vivo, and in 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 to tumor proliferation. The anti-cancer 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.