Efficacy of 9-cis retinoic acid (9-cis-RA) in preventing methylnitrosourea (MNU)-induced mammary cancers

Chemopreventive agents inhibit the process of carcinogenesis. 9- cis Retinoic Acid (9-cis-RA) is known to be an effective inhibitor of cancer formation in the mammary gland. The biochemical mechanism(s) involved, however, are not understood. At the beginning of this effort, it was unclear how 9-cis-RA, at various dose levels or in combination with other chemopreventive agents, affected cancer incidence in the MNU-induced mammary cancer model.; In an initial study, conducted with animals that received a range of 9-cis-RA dose levels, a dose-dependent response was found within the groups. Another study demonstrated that, to achieve a strong chemopreventive effect, 9-cis-RA had to be administered continuously.; To investigate the effects of 9-cis-RA combined with N-(4-hydroxyphenyl)-retinamide (4-HPR), younger animals were administered agents in the diet, starting at 53 days of age. The combination caused significant reductions in cancer incidence and number per animal. Older animals (administered agents in the diet at 93 days of age) showed an even greater effect when treated with the combination of 4-HPR and 9-cis-RA.; Another study was designed to determine if the combination of vitamin D3 with 9-cis-RA would inhibit mammary carcinogenesis in young rats. The two groups of animals fed vitamin D3 alone had no reductions in mammary cancer compared to controls. When combined with 9-cis-RA, however, both dose levels of vitamin D3 inhibited mammary cancer to a greater extent than 9-cis-RA alone.; A final study was conducted in an attempt to understand the mechanism(s) in which 9-cis-RA may decrease mammary cancers. The diets of animals were supplemented with 9-cis-RA for either 3 days or 4 weeks, and various parameters were evaluated. Mammary epithelial cells were isolated from the animals, and the total RNA was extracted. mRNA expression for the retinoid nuclear receptor, retinoic acid receptor β (RARβ), was measured in the epithelial cells; no differences in expression were found among the groups. Morphologic evaluation of the mammary glands showed no increased differentiation in rats treated with 9-cis-RA.; In conclusion, these studies showed that 9-cis-RA, at various dose levels, alone and in combination with other chemopreventive agents strongly inhibited MNU-induced mammary cancer. Additional studies are needed to determine the mechanism(s) involved in this effect.