Gene Regulation and Expression Pattern of the Growth Factor Pleiotrophin in Breast Cancer

The growth factor plelotrophin is a positive regulator of tumor angiogenesis and is expressed in breast cancer cell lines and in primary tumor specimens and is one of the factors for the malignant phenotypes of human mammary carcinoma. The expression of PTN in normal and pathologic human breast tissue is mediated by co expression of the species specific transcript and the HERV-PTN fusion transcript. The transcription factor YYl strongly represses HERV-PTN fusion transcript in two breast cancer cell lines. In an effort to understand the biological and biochemical effects of PTN, we recently found that it exerts its action through an orphan membrane tyrosine kinase receptor, anaplastic lymphoma kinase (ALK). We present evidence that ALK is activated by PTN and, sequentially, activates an array of second messengers in various cell lines. Interestingly, human primary mammary fibroblasts express ALK, and Akt and MA%K are activated upon addition of PTN. ALK expression levels are important for the tumorigenicity of cell lines that expresses PTN also. Upregulated levels of ALK in HUVEC render these cells more susceptible to PTN and promote angiogenesis. We conclude that expression of PTN in human mammary cells leads to activation of ALK in stromal cells and promote tumor growth.