The t10,c12 isomer of conjugated linoleic acid stimulates mammary tumorigenesis in transgenic mice over-expressing erbB2 in the mammary epithelium.
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.
Ip
Margot M
MM
Department of Pharmacology and Therapeutics and Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. margot.ip@roswellpark.org
McGee
Sibel O
SO
Masso-Welch
Patricia A
PA
Ip
Clement
C
Meng
Xiaojing
X
Ou
Lihui
L
Shoemaker
Suzanne F
SF
D000818:Animals; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D007536:Isomerism; D044243:Linoleic Acids, Conjugated / Q000009:adverse effects*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000556:secondary; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*
D044243:Linoleic Acids, Conjugated; D018719:Erb-b2 Receptor Tyrosine Kinases; C496197:trans-10,cis-12-conjugated linoleic acid