Pleiotrophin as a Growth Factor and Therapeutic Target in Breast Cancer.

Under goal 1 of this award we studied the mechanisms of regulation of the pleiotrophin PTN gene. We discovered a germ line retroviral insertion that contributes to the transcriptional regulation of this gene. Phylogenetic analysis showed that the retroviral insertion happened approximately 25 million years ago and affects tissue-specific expression of the gene. The same retroviral element was found inserted into the human BRCA-1 gene locus suggesting some overlapping regulation mechanisms between the two genes. Under goal 2 the effects of PTN expression were studied and found to contribute to tumorigenicity of non-expressing cells. Under goal 3 we analyzed the functional domains of the PTN protein and studied its signal transduction. We showed that MAP kinase PI 3-kinase pathways are used for mitogenesis and identified candidate receptor proteins. Most recently, we identified a PTN receptor candidate and now report data on the effects of targeting and depletion of this receptor from human breast cancer cells that express PTN as well as from cells that respond to PTN. We found that the tumor cells utilize the PTN PTN-receptor interaction in an autocrine manner. Furthermore, we show that depletion of the receptor mRNA also abolishes the ability of PTN to stimulate growth of receptor positive cells. Under goal 4 we studied the effects of the repression of PTN production on the tumorigenic phenotype and showed that PTN expression is rate-limiting for tumor growth, invasion, angiogenesis and metastasis.