In Vitro and In Vivo Effects of Conjugated Linoleic Acid on Mammary Tumorigenesis

摘要

Conjugated linoleic acid (CLA) exhibits multiple biological and molecular activities that have made it the subject of considerable nutrition-related research. Numerous studies support broad acting anti-tumor effects including anti-inflammatory, anti-proliferation, and pro-apoptosis in a variety of model systems. CLA’s ability to influence multiple tumor promoting pathways, without toxicity, may prove valuable in the chemoprevention of breast cancer. The overall objective of this dissertation research was to investigate the potential of CLA in the chemoprevention of breast cancer in a subgroup of women at risk of developing estrogen receptor (ER) negative disease. Overexpression of either the ERBB2 oncogene or the epidermal growth factor receptor (EGFR) is a common event in ER negative breast cancer. To respond to this association, the stated research objective was pursued in relevant model systems. The primary hypothesis was that CLA would downregulate the ERBB2 receptor in vitro and inhibit mammary tumorigenesis in vivo. The t10c12 CLA isomer significantly reduced ERBB2 protein expression in the ERBB2 overexpressing cell line SKBr3. This was accompanied by a decrease in NFκB nuclear localization, cyclooxygenase-2 (COX2)-derived prostaglandin (PG) E2 production, increased apoptosis, and inhibition of proliferation. In contrast to the in vitro data, however 1% dietary CLA had pro-tumor effects in the PyV-mT transgenic mouse model, Mammary gland whole mounts indicated a significant loss of adipose in the CLA-treated group compared to controls that was confirmed by the downregulation of adipocyte-specific genes including PPARγ and adiponectin. CLA’s effect on the adipose was supported by decreases in fatty acid synthase at the protein and mRNA level. cDNA microarray revealed significant downregulation of cytoskeletal and adhesion-related genes in the CLA-treated group. These data suggest CLA’s combined effect on the adipose and epithelial architecture may have promoted tumor growth in this model While the large body of evidence supporting an anti-tumor effect of CLA can not be discounted, the studies herein demonstrate the complexity of its action that may not be captured in simple model systems. Reports of adverse effects of mixed isomers or the t10c12 purified isomer lend caution to supplementation that is supported by our in vivo data.