Increasing evidence suggests mutations in human
breast cancer cells that induce inappropriate expression of the 18-kDa
cytokine pleiotrophin (PTN, Ptn) initiate progression of breast
cancers to a more malignant phenotype.
Pleiotrophin signals through inactivating its receptor, the receptor
protein tyrosine phosphatase (RPTP)beta/zeta, leading to increased
tyrosine phosphorylation of different substrate
proteins of
RPTPbeta/zeta, including
beta-catenin,
beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP. PTN signaling thus has wide impact on different important cellular systems. Recently, PTN was found to activate
anaplastic lymphoma kinase (ALK) through the PTN/
RPTPbeta/zeta signaling pathway; this discovery potentially is very important, since constitutive ALK activity of
nucleophosmin (
NPM)-ALK fusion protein is causative of
anaplastic large cell lymphomas, and, activated ALK is found in other malignant
cancers. Recently ALK was identified in each of 63 human breast
cancers from 22 subjects. We now demonstrate that
RPTPbeta/zeta is expressed in each of these same 63 human breast
cancers that previously were found to express ALK and in 10 additional samples of human
breast cancer.
RPTPbeta/zeta furthermore was localized not only in its normal association with the cell membrane but also scattered in cytoplasm and in nuclei in different
breast cancer cells and, in the case of infiltrating
ductal carcinomas, the distribution of
RPTPbeta/zeta changes as the
breast cancer become more malignant. The data suggest that the PTN/
RPTPbeta/zeta signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human
breast cancer.