Carcinogenesis Advance Access originally published online on March 13, 2008
Carcinogenesis 2008 29(5):1013-1021; doi:10.1093/carcin/bgn035
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t10,c12-Conjugated linoleic acid stimulates mammary tumor progression in Her2/ErbB2 mice through activation of both proliferative and survival pathways
1 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
2 School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515 China
* To whom correspondence should be addressed. Tel: +1 716 845 2356; Fax: +1 716 845 5865;Email: 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% trans-10, cis-12 conjugated linoleic acid (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 to 4.6 weeks. Short-term supplementation from 10 to 14 weeks or 21 to 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 mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways; however, neither phospho-ErbB2 nor ErbB2 was altered.
Abbreviations: CLA, conjugated linoleic acid; c9,t11-CLA, cis-9, trans-11 CLA; ERK, extracellular signal-regulated kinase; H&E, hematoxylin and eosin; IGF-IR, insulin-like growth factor I receptor; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3-kinase; PMN, polymorphonuclear leukocyte; TEB, terminal end bud; t10,c12-CLA, trans-10, cis-12 CLA
Received October 25, 2007; revised December 31, 2007; accepted January 24, 2008.