Conjugated Linoleic Acid Induces Mast Cell Recruitment during Mouse Mammary Gland Stromal Remodeling1

Abstract

Conjugated linoleic acid (CLA) is a dietary chemopreventive agent that induces apoptosis in the mammary adipose vascular endothelium and decreases mammary brown adipose tissue (BAT) and white adipose tissue (WAT). To determine onset and extent of stromal remodeling, we fed CD2F1/Cr mice diets supplemented with 1 or 2 g/100 g mixed CLA isomers for 1-7 wk. BAT loss, collagen deposition, and leukocyte recruitment occurred in the mouse mammary fat pad, coincident with an increase in parenchymal-associated mast cells in mice fed both levels of CLA. Feeding experiments with purified isomers (0.5 g/100 g diet) demonstrated that these changes were induced by trans-10, cis-12 CLA (10,12-CLA), but not by cis-9, trans-11 CLA (9,11-CLA). This stromal remodeling did not require tumor necrosis factor (TNF)-alpha, a major cytokine in mast cells, as TNF-alpha null mice demonstrated collagen deposition, increased leukocytes, and BAT loss in the mammary fat pad in response to 10,12-CLA. To test the hypothesis that mast cells recruited in response to 10,12-CLA were required for stromal remodeling, Steel mice (WBB6F1/J-kit(W)/kit(W-V)), which lack functional mast cells, were examined for their stromal response to 10,12-CLA. Both wild-type and Steel mice showed a significantly increased leukocytic adipose infiltrate, collagen deposition, and decreased adipocyte size, although BAT was maintained in Steel mice. These results demonstrate that 10,12-CLA induces an inflammatory and fibrotic phenotype in the mouse mammary gland stroma that is independent of TNF-alpha or mast cells and suggest caution in the use of 10,12-CLA for breast cancer chemoprevention.

Immunohistochemical Study of Calretinin in Normal Skin and Cutaneous Adnexal Proliferations

“…However, we found calretinin positivity in stromal cells of the lesion, which were mast cells, possibly involved in the remodeling of mammary tissue. 16,17 Therefore, immunostaining with calretinin might have utility on this respect. In syringocystadenoma papilliferum, the luminal epithelial cell layer lining the papillary structures and the tubules shows unequivocal signs of decapitation secretion.…”

Effects of Ruminant trans Fatty Acids on Cardiovascular Disease and Cancer: A Comprehensive Review of Epidemiological, Clinical, and Mechanistic Studies

“…In a transplantable mouse model with mammary tumor and spontaneous lung metastasis, CLA [mixture of isomers: c9,t11-CLA (32.5 g/ 100 g), t10,c12-CLA (33.5 g/100 g), 18:1 (18 g/100 g), and other isomers (16 g/100 g)] reduced the metastasis rate, total tumor burden, and the survival of metastatic cells, in a dosedependent manner, without affecting primary tumor growth (130). However, several other studies have demonstrated no effect of c9,t11-CLA, particularly on latency in mice bearing mammary tumors (130)(131)(132)(133). Data from cell culture studies have demonstrated antiproliferative effects of CLA in MCF-7 breast cancer cells (134,135), possibly due to effects on PPARg and E-cadherin/b-catenin pathways (136).…”

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

“…It was expected that the 10,12-CLA isomer would specifically induce an increase in mast cell number or differentiation, based on the previous observation that this CLA isomer significantly increases mast cell abundance in the mouse mammary gland (Russell et al, 2007). We hypothesized that the effects of CLA may be directly mediated through its effects on mast cells.…”

“…We have found their abundance increased in mouse mammary gland specifically in response to feeding with trans10,cis12-CLA (10,12-CLA), coincident with fibrosis and leukocyte recruitment (Russell et al, 2007). This in vivo effect was specific to 10,12-CLA and not seen with cis9,trans11-CLA (9,11-CLA).…”

“…Based on the previously described activity of 10,12-CLA to increase mast cell number in mouse mammary gland tissue (Russell et al, 2007), we hypothesized that 10,12-CLA may have direct effects to stimulate mast cell growth in vitro. In contrast to our expectations, both isomers of CLA decreased viable mast cell number in vitro, by MTT assay.…”