RESUMO
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.
