PREVENTION OF BREAST-CANCER IN THE RAT WITH 9-CIS-RETINOIC ACID AS A SINGLE-AGENT AND IN COMBINATION WITH TAMOXIFEN

We show that 9-cis-retinoic acid (9cRA) is a potent inhibitor of mamma ry carcinogenesis induced by N-nitroso-N-methylurea in Sprague-Dawley rats. Rats were first treated with a single dose of N-nitroso-N-methyl urea (50 mg/kg body weight) and then fed non-toxic levels of 9cRA (120 or 60 mg/kg of diet). 9cRA was highly effective in reducing tumor inc idence, average number of tumors per rat, and average tumor burden, as well as extending tumor latency. The combination of 9cRA with low lev els of tamoxifen (TAM; fed at either 1.0 or 0.5 mg/kg of diet) was par ticularly effective; addition of 9cRA to a TAM regimen doubled the num ber of animals that were tumor-free at autopsy and significantly dimin ished tumor number and tumor burden. For suppression of carcinogenesis ill vivo, 9cRA was much more potent than all-trans-retinoic acid, bot h as a single agent or in combination with TAM, although both retinoid s had equivalent inhibitory effects on DNA synthesis in cultured human breast cancer cell lines. Both 9cRA and all-trans-retinoic acid induc e the expression of the adhesion molecule, E-cadherin, in the SKBR-3 c ell line. We suggest that clinical evaluation of the combination of 9c RA and TAM, either for chemoprevention or for adjuvant therapy, should be considered.