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

We hypothesized that specific activation of a single retinoic acid receptor-alpha (RARalpha), without direct and concurrent activation of RARbeta and gamma, 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 RARalpha 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 beta-catenin, suggesting partial oncogene dependence of therapy. Am580 treatment increased RARbeta and lowered the level of RARgamma, an isotype whose expression we linked with tumor proliferation. The anticancer effect of RARalpha, together with the newly discovered pro-proliferative role of RARgamma, suggests that specific activation of RARalpha and inhibition of RARgamma might be effective in breast cancer therapy.