Conjugated linoleic acid (abbreviated to CLA) represents a family of 18-carbon fatty acid isomers with two conjugated double bonds. CLA exerts a powerful anticancer activity in the rat mammary gland. Our current working model is built on the concept that CLA is able to affect different cell populations of the mammary tissue. In addition to suppressing neoplastic progression of the epithelial cells, CLA also targets the mammary stromal cells in blocking their differentiation to endothelial cells. The latter outcome results in reduced angiogenesis, thereby contributing to cancer protection by CLA. There is an increasing awareness that one CLA isomer may produce specific biological effects not shared by the other. The paucity of information on the anticancer effect of 9,11-CLA versus 10,12-CLA provides the justification for comparing the cellular and molecular responses to these two isomers in both mammary epithelial and mammary stromal populations.
Aim 1 is to study the anticancer and biomarker modulatory effects 9,11-CLA and 10,12- CLA in the rat mammary gland. Specifically proliferation and apoptosis biomarkers will be evaluated in premalignant lesions before they progress to carcinomas. The knowledge on biomarkers will be very valuable because these targets could be used as surrogate endpoints to assess the efficacy of CLA in future intervention trials. There are limitations in using the whole mammary gland as an organ to do molecular analysis. We have therefore included a mammary cell culture model to elucidate the cellular effects of CLA, such as cell cycle perturbation, clonogenic growth inhibition and induction of apoptosis, as well as the molecular basis responsible for these cellular events. Fatty acids are ligands for a class of transcription factors called peroxisome proliferator-activated receptors (PPAR), and both 9,11-CLA and 10,12-CLA have been demonstrated to be high-affinity ligands and activators of PPAR.
Aim 2 is to investigate the role of different PPAR subtypes as signaling pathways for CLA responses in blocking proliferation and inducing apoptosis in an in vitro rat mammary tumor cell model. Experiments will be designed to address the ability of 9,11-CLA and 10,12-CLA in modulating the expression, nuclear translocation, DNA-binding and transcriptional activity of individual PPAR subtype, and whether PPAR activation contributes to the anticancer effect of CLA. Lastly, Aim 3 is to determine the functional consequence of CLA alteration of the mammary stroma on the angiogenic switch during rat mammary carcinogenesis and on the hematogenous and lymphogenous spread of transplantable metastatic rat mammary tumors.
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