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Carcinogenesis Advance Access published online on March 13, 2008
Carcinogenesis, doi:10.1093/carcin/bgn035
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

t10,c12-conjugated linoleic acid stimulates mammary tumor progression in her2/erbB2 mice through activation of both proliferative and survival pathways

Xiaojing Meng*,{ddagger}, Suzanne Shoemaker*, Sibel O. McGee* and Margot M. Ip*

* Departments of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY
{ddagger} School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China

Correspondence: Dr. Margot Ip, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: Margot.Ip{at}RoswellPark.org

The t10,c12 isomer of conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis, metastasis from a transplantable mouse mammary tumor, and angiogenesis; however it stimulates mammary tumorigenesis in transgenic mice overexpressing ErbB2 in the mammary epithelium (ErbB2 transgenic mice). In the current study, we report that a 4 week supplementation of the diet with 0.5% t10,c12-CLA stimulated the growth of established ErbB2-overexpressing mammary tumors by 30%, and increased the number of new tumors from 11 to 82%. Additionally, when t10,c12-CLA supplementation of ErbB2 transgenic mice was initiated at 21 weeks of age, a time just prior to tumor appearance, overall survival was decreased from 46.4 weeks in the control to 39.0 weeks in the CLA group, and survival after detection of a palpable tumor from 7.5 weeks to 4.6 weeks. Short-term supplementation from 10-14 or 21-25 weeks of age temporarily accelerated tumor development, but over the long-term, there was no significant effect on mammary tumorigenesis. Long-term as well as a short 4 week supplementation increased mammary epithelial hyperplasia and lobular development, and altered the mammary stroma; this was reversible in mice returned to the control diet. t10,c12-CLA altered proliferation and apoptosis of the mammary epithelium, although this differed depending on the length of administration and/or the age of the mice. The increased tumor development with t10,c12-CLA was associated with increased phosphorylation of the IGF-I/insulin receptor, as well as increased signaling through the MEK/ERK and PI3K/Akt pathways; however, neither phospho-ErbB2, nor ErbB2, were altered.

Received October 25, 2007; revised December 31, 2007; accepted January 24, 2008.


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