t10,c12-Conjugated linoleic acid stimulates mammary tumor progression in Her2/ErbB2 mice through activation of both proliferative and survival pathways

Abstract

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.

Mammary gland development—It’s not just about estrogen

“…When we co-administered the IGF-1R inhibitor picropodophyllotoxin to OVX mice fed 10,12 CLA, ductal elongation was abrogated, indicating that activation of the IGF-1R was indeed necessary during this induction of MG growth. In support of these findings, phosphorylation of the IGF-1R/insulin receptor was increased in MG tumors from 10,12 CLA-fed mice overexpressing ErbB2 (Meng et al, 2008). …”

“…These changes include the increased local deposition of collagen (Russell et al, 2007), the recruitment of immune cells including macrophages and mast cells (Poirier et al, 2006; Russell et al, 2007; Shen et al, 2013), and an inflammatory state at both the systemic and tissue levels that manifests as decreased serum adiponectin (Purushotham et al, 2007) and elevated IL-6 and tumor necrosis factor-α mRNA in adipose tissue (Poirier et al, 2006; Shen et al, 2013). At the same time, the volume of the supramammary lymph nodes within the MG is increased by dietary 10,12 CLA, along with significant splenomegaly (Meng et al, 2008) and splenocyte proliferation (Hayek et al, 1999). The local inflammatory phenotype induced by dietary 10,12 CLA is also dose-dependent (Foote et al, 2010; Li et al, 2012; Shen et al, 2013).…”

t10,c12-CLA decreases adiposity in peripubertal mice without dose-related detrimental effects on mammary development, inflammation status, and metabolism

“…In contrast, the 0.5% 10,12-CLA diet induced the emergence of buds along the entire ductal tree, and this morphological abnormality was associated with a doubling in the abundance of the marker of epithelial cell mass K18, suggesting increased proliferation. This is supported by increased Ki67 labeling in the TEB-like structures reported for the mammary glands of mature virgin mice consuming a 0.5% 10,12-CLA diet (27). The budding structures decorating the ducts in the 0.5% 10,12-CLA Fig.…”

Direct Effects of Conjugated Linoleic Acid Isomers on P815 Mast Cells in vitro

“…Despite abundant studies (reviewed in (Ip et al, 2003)) showing cancer protective effects of CLA in the rat mammary gland (a more relevant model for the human breast (reviewed in Medina and Thompson, 2000), studies in the mouse have shown different responses, both in normal stromal response (Russell et al, 2007;Tsuboyama-Kasaoka et al, 2000) as well as in limited effect on primary tumor growth (Hubbard et al, 2003(Hubbard et al, , 2006 or actual tumor stimulatory effects Meng et al, 2008).…”