Conjugated linoleic acid (CLA) represents certain positional isomers of linoleic acid. Milk and dairy products are good sources of CLA because of the unique metabolic capability of rumen bacteria in converting linoleic acid to CLA. We have described two distinct activities of CLA in mammary cancer prevention. First, CLA down-regulates mammary gland morphogenesis, and in doing so, may lower cancer risk. Second, CLA is also capable of suppressing neoplastic progression. Additionally, our in vitro experiments show that CLA decreases cell growth and induces apoptosis in a primary mammary epithelial cell (MEC) culture system.
Aim 1 will determine the mechanism by which CLA inhibits proliferation of MEC. It is postulated that CLA may modulate signal transduction pathways. Potential targets include activation and recruitment of G proteins to the plasma membrane, the activity of the MAP kinase family, cyclins, cdk inhibitors and Rb.
Aim 2 will determine the mechanism by which CLA stimulates apoptosis of MEC. The expression and activity of specific caspases, and the ability of caspase inhibitors to attenuate the apoptotic response to CLA, will be investigated. Additionally, the expression, phosphorylation, and dimerization of pro- and anti-apoptotic proteins will be studied.
Aim 3 will determine whether CLA alters stromal-epithelial interactions since CLA is highly enriched in mammary adipocytes. A mammary adipocyte co-culture model will be utilized to delineate the effect of CLA-loaded adipocytes on the proliferation, differentiation, and apoptosis of normal and transformed MEC. Follow-up studies will investigate whether MEC transplanted into the gland-free mammary fat pad of CLA pre-treated rats are growth inhibited.
Aim 4 will determine how CLA might affect the pace and outcome of mammary gland development and to elucidate the biological significance in relation to modulation of cancer risk. These animal experiments are designed to address whether CLA nutrition during pubescence may have a durable suppressive effect on maturation of the mammary epithelium and therefore resulting in a lower cancer risk later on in life.
Aim 5 will determine the effect of CLA feeding on the expression of proliferative and apoptotic markers in defined target cell populations of the mammary gland. These studies are designed to apply the in vitro information of Aims 1 and 2 to the in vivo model in order to validate the use of molecular surrogate endpoints in CLA intervention.
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