We tested whether specific activation of a single retinoic acid receptor, RAR alpha (RARα), without direct activation of RAR beta (RARβ) and gamma (RARγ), will inhibit mammary tumor oncogenesis in murine models relevant to human cancer. Fifty MMTV-neu (neu), 30 MMTV-myc (myc), and 50 MMTV-wnt1 (wnt1) transgenic mice were treated with 0.3mg/Kg/day RARα agonist, (retinobenzoic acid, Am580), added to the diet for 40 (neu), 50 (myc) and 35 weeks (wnt1), respectively. Different responses to the treatment were observed in the 3 mouse models, the wnt1 the more responsive, the neu with a mild response and a subset of the myc refractory to the treatment. Among the anti-tumor effects observed in the wnt1 and neu models was the inhibition of epithelial hyperplasia, a significant increase (p<0.05) in tumor-free survival, a reduction in tumor incidence and in growth of established tumors and lung metastasis dissemination (neu model, p<0.001). In both models the mechanisms responsible for these effects involved inhibition of proliferation and survival pathways, and induction of apoptosis. The stronger wnt1 response to Am580 also induced differentiation, both in vivo, and in 3D cultures. In these tumors Am580 inhibited the wnt-pathway, measured by loss of nuclear b-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. Interestingly, the myc mice showed a more complex response in which no significant effect was observed on tumor development but a clear reduction on tumor growth (p<0.001) and lung metastasis dissemination (p<0.01) in a subset of mice (63%). Immunohistological analysis showed scattered necrotic foci, induction of Cyp26A1, E-cadherin, CRBP1 and p27, known RARα response genes, suggesting that cell death, growth inhibition and differentiation are involved in the anti-tumor effect of Am580 in this model. As in the neu and wnt1 models, RARγ was overexpressed in the myc tumors, genetic and pharmacological approaches inhibiting RARγ expression and activity resulted in growth inhibition and differentiation in vitro (2D and 3D cultures). Finally, forced expression of CRBP1 in myc tumor derived cells inhibited tumor growth in xenografts (60%, p<0.05) suggesting that the induction of CRBP1 expression by Am580 can be, in part, responsible for the anti-tumor effect. 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.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4615.