Clinically relevant animal models of mammary
carcinogenesis are crucial for the development and evaluation of new
breast cancer chemopreventive agents. The neu-induced retroviral rat mammary
carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary
carcinomas in intact Wistar-Furth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, approximately 50% of mammary
carcinomas can be prevented by
tamoxifen treatment. In ovariectomized animals, the mammary
carcinomas are hormonally nonresponsive and cannot be prevented by
tamoxifen. We evaluated the efficacy of retinoic X receptor-selective
retinoids (rexinoids) in this novel model of mammary
carcinogenesis. The rexinoids
LG100268 and
bexarotene (LG1069,
Targretin) were highly efficacious in the prevention of neu-induced mammary
carcinomas. Dietary
LG100268 at 100 mg/kg diet decreased
tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats.
Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in
tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to
tumor multiplicity, proliferation and apoptosis were modulated by
bexarotene treatment independently of
estrogen signaling. The neu-induced retroviral rat mammary
carcinogenesis model represents a valuable addition to existing rodent
chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive
tumors.