The t10,c12 isomer of conjugated linoleic acid stimulates mammary tumorigenesis in transgenic mice over-expressing erbB2 in the mammary epithelium

Abstract

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.

Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss

“…Since dietary CLA is incorporated into mammary adipocyte triglycerides, it may be possible to achieve an effective local concentration of c9,t11-CLA in the in vivo setting. This is an important consideration, given the potentially serious side effects of t10,c12-CLA seen in some, although not all studies, including our recent observation that t10,c12-CLA stimulates mammary tumorigenesis and metastasis in mice which overexpress erbB2 in the mammary epithelium ( [33] and references within). Work is continuing in our laboratory on the mechanism by which the individual CLA isomers exert their effects, with the goal of defining an optimal CLA strategy for chemoprevention.…”

Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice

“…At sacrifice, mammary glands and tumors were removed and prepared for whole mount analysis and/or fixed in formalin. Lungs of the euthanized mice were perfused with India ink through the trachea, removed, and fixed as described previously (20).…”

“…Whole mounts of the mammary glands were prepared as described previously (20). Using photographic images of the whole mounts, with verification under the 4× objective of the microscope, the number of hyperplasias/lesions in mammary glands 1 to 5 on one side of each mouse was counted in three groups according to size (0.2-0.5, 0.5-1.0, and >1.0 mm in diameter).…”

“…Using photographic images of the whole mounts, with verification under the 4× objective of the microscope, the number of hyperplasias/lesions in mammary glands 1 to 5 on one side of each mouse was counted in three groups according to size (0.2-0.5, 0.5-1.0, and >1.0 mm in diameter). Lung metastases, H&E staining, Ki67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) immunohistochemistry, and photography were as described previously (20), with the exception that the Ki67 antibody (RM-9106-S1) was purchased from Neomarkers/Lab Vision. The percentages of Ki67-positive or TUNEL-positive cells were quantified in 117 to 120 lobules, ducts, or microscopic hyperplasias/putative neoplastic lesions in the mammary epithelium.…”

In vitro study of dietary factors affecting the biohydrogenation shift from trans-11 to trans-10 fatty acids in the rumen of dairy cows

“…Part of the effects of CLA are isomer-specific and some studies showed adverse effects of t10,c12-CLA (Bhattacharya et al, 2006;Ip et al, 2007). Similarly, total trans fatty acids (FA), including monoenoic, can alter cardiovascular risk markers; however, the specificity of individual isomers remains an area of controversy, where some suggest a similar effect of all trans FA (Brouwer et al, 2010), whereas others assume natural trans FA, mainly of milk origin, are less deleterious as compared with industrial trans FA (Tardy et al, 2011).…”