Study summary: The present study was designed to test the efficacy of two conjugated linoleic acid (CLA) isomers in a clinically relevant breast cancer model. CLA has been shown to inhibit 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 found in CLA supplements, have been found to be equally effective. Experimental erbB2 transgenic mice were fed either a control diet or a 0.5% CLA-supplemented diet after weaning. It was found that t10,c12-CLA unexpectedly stimulated lobular hyperplasia of the mammary epithelium and accelerated mammary tumor development. The t10,c12-CLA diet decreased median tumor latency to 168 days of age compared to 256 and 270 days in the c9,t11-CLA and control diet groups, respectively. Metastasis was also found to be increased by t10,c12-CLA, with the percentage of tumor-bearing mice with lung metastasis found to be 73%, 14% and 31% in the t10,c12-CLA, c9,t11-CLA and control groups, respectively. A second study was performed in which CLA administration was initiated after puberty. This study confirmed the cancer-promoting effect of t10,c12-CLA. In addition, t10,c12-CLA (but not c9,t11-CLA) increased the size of the mammary liver, heart, spleen and lymph node. The effects of t10,c12-CLA were not specific to the erbB2 transgenic mice, as t10,c12-CLA supplementation also increased proliferation in the mammary epithelium of wild-type FVB mice and FVB/erbB2 mice as well. In fact, the number of terminal end buds, the mammary epithelial structures most sensitive to a carcinogens, was increased 30-fold in FVB wild-type mice fed t10,c12-CLA. The authors conclude 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 some rat models suggests that it may have activity for prevention of some types of breast cancer.