No abstract

Conjugated linoleic acid (CLA), a family of isomers of octadecadienoic acid, inhibits rat mammary carcinogenesis, angiogenesis, and lung metastasis from a transplantable mammary tumor. c9,t11-CLA, the predominant isomer in dairy products, and t10,c12-CLA, a component of CLA supplements, are equally effective. The objective of the current studies was to test the efficacy of these two CLA isomers in a clinically relevant breast cancer model. Transgenic mice over-expressing erbB2 in the mammary epithelium were fed control or 0.5% CLA-supplemented diets continuously from weaning. Unexpectedly, t10,c12-CLA stimulated lobular hyperplasia of the mammary epithelium and accelerated mammary tumor development, decreasing median tumor latency to 168 days of age compared with 256 and 270 days in the c9,t11-CLA and control groups, respectively. Metastasis was also increased by t10,c12-CLA, with percentage of tumor-bearing mice with lung metastasis 73, 14 and 31% in the t10,c12-CLA, c9,t11-CLA and control groups, respectively. A second study, in which CLA administration was initiated after puberty, confirmed the stimulatory effect of t10,c12-CLA on mammary tumor development and metastasis. Additionally, t10,c12-CLA, but not c9,t11-CLA, increased the size of the liver, heart, spleen and mammary lymph node. The effects of t10,c12-CLA were not specific to erbB2 transgenic mice, as t10,c12-CLA supplementation increased proliferation in the mammary epithelium of both wild-type FVB and FVB/erbB2 mice. Moreover, the number of terminal end buds, the mammary epithelial structures most sensitive to a carcinogenic insult, was increased 30-fold in FVB wild-type mice fed t10,c12-CLA. These data suggest that it would be prudent to avoid CLA supplements containing the t10,c12-CLA isomer. However, even though c9,t11-CLA was not efficacious in the erbB2 model, its ability to inhibit mammary tumor development in rat models suggests that it may have activity for prevention of some types of breast cancer.

The effects of the cyclooxygenase inhibitors indomethacin and carprofen on the enhancement of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis by dietary linoleate have been compared in female Sprague-Dawley rats. Indomethacin and carprofen, 0.004% and 0.02% (w/w) in the diet, respectively, were fed to rats receiving 20% fat diets containing 0.5, 4 or 12% linoleate starting 7 days after administration of 5 mg DMBA i.g. Indomethacin was shown to have a marked inhibitory effect on mammary tumorigenesis in rats fed the 4 and 12% linoleate diets, but did not alter tumorigenesis in rats fed the 0.5% linoleate diet. In contrast, carprofen was not inhibitory in any of these dietary groups, or in a separate experiment in which a 5% fat--3% linoleate diet was fed. The effect of each drug on prostaglandin E2 (PGE2) levels in normal mammary glands enriched in epithelial cells after a 3-week pretreatment with 17 beta-estradiol and progesterone was also investigated. Carprofen was shown to reduce PGE2 levels to a similar or greater extent than indomethacin at each level of linoleate in the diet. These data demonstrate that a reduction in PGE2 synthesis in the mammary epithelium does not correlate with inhibition of mammary tumorigenesis, and that other factors, including possible alterations in other products of the arachidonic acid cascade, are responsible for this inhibitory effect.

There is increasing evidence that individual isomers of conjugated linoleic acid (CLA) may have unique biological or biochemical effects. A primary objective of this study was to determine whether there might be differences in the anticancer activity of 9,11-CLA and 10,12-CLA. This was achieved by evaluating the reduction in premalignant lesions and carcinomas in the mammary gland of rats that had been treated with a single dose of methylnitrosourea and given 0.5% of either highly purified CLA isomer in the diet. Our results showed that the anticancer efficacies of the two isomers were very similar. At 6 wk after carcinogen administration, the total number of premalignant lesions was reduced by 33-36%. At 24 wk, the total number of mammary carcinomas was reduced by 35-40%. The concentration of each CLA isomer and its respective metabolites was analyzed in the mammary fat pad. Tissue level of 10,12-CLA was much lower than that of 9,11-CLA. The pool of metabolites from each isomer was very similar between the two groups and represented only a small fraction of total conjugated diene fatty acids. Feeding of 9,11-CLA resulted in minimal changes in other unsaturated fatty acids. In contrast, feeding of 10,12-CLA produced a wider spectrum of perturbations. Small but significant increases in 16:1 and 16:2 were detected; these were accompanied by decreases in 20:2, 20:3, 20:4, 22:4, and 22:6. The above observation suggests that 10,12-CLA might be more potent than 9,11-CLA in interfering with elongation and desaturation of linoleic and linolenic acids. In summary, our study showed that, at the 0.5% dose level, the anticancer activity of 9,11-CLA and 10,12-CLA was very similar, even though accumulation of 10,12-CLA in the mammary tissue was considerably less than that of 9,11-CLA. These confounding changes of the other unsaturated fatty acids in contributing to the effect of 10,12-CLA need to be clarified.

The mammary gland is a dynamic tissue that undergoes epithelial expansion and invasion during puberty and cycles of branching and lobular morphogenesis, secretory differentiation, and regression during pregnancy, lactation, and involution. The alteration in the mammary gland epithelium during its postnatal differentiation is accompanied by changes in the multiple stromal cell types present in this complex tissue. The postnatal plasticity of the epithelium, endothelium, and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The purpose of this review is to assist researchers in recognizing histological changes in the epithelium and stroma of the rat mammary gland throughout development.