The receptor protein tyrosine phosphatase (RPTP)β/ζ is expressed in different subtypes of human breast cancer

Abstract

Increasing evidence suggests mutations in human breast cancer cells that induce inappropriate expression of the 18kDa 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)β/ζ, leading to increased tyrosine phosphorylation of different substrate proteins of RPTPβ/ζ, including β-catenin, β-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/RPTPβ/ζ 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 RPTPβ/ζ 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. RPTPβ/ζ 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 RPTPβ/ζ changes as the breast cancer become more malignant. The data suggest that the PTN/RPTPβ/ζ signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human breast cancer.

Adipocyte derived paracrine mediators of mammary ductal morphogenesis controlled by retinoic acid receptors

“…Thus, adipose RAR induces PTHR expression and this leads to increased expression of PTN which in turn regulates mammary epithelial migration. Although, several receptors for PTN have been described, cell migration has been shown to be induced through PTN binding to a protein tyrosine phosphatase receptor ζ1 (also referred to as PTPRβ/ζ) (Ulbricht et al, 2003) with a second receptor ALK, being now considered a downstream substrates for PTPRζ1 (Perez-Pinera et al, 2007). Binding of PTN to PTPRζ1 receptor inactivates the receptor phosphatase activity, causing increased phosphorylation of target proteins.…”

Receptor Tyrosine Phosphatase β (RPTPβ) Activity and Signaling Are Attenuated by Glycosylation and Subsequent Cell Surface Galectin-1 Binding

“…Aberrant expression of the embryonic long receptor form of RPTP␤ in invasive glioblastoma likely contributes to the highly invasive phenotype of this tumor (56). Moreover, this form of RPTP␤ has also been consistently found expressed in different subtypes of human breast cancer, suggesting that its expression, and perhaps glycosylation, may affect the adhesion of non-neural carcinomas (57).…”

Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

“…Furthermore, the full-length ALK cDNA was originally cloned from an Rh30 rhabdomyosarcoma cell line cDNA library [5,17,19], and expression of the full-length protein has subsequently been reported to occur in a subset of rhabdomyosarcoma tumors [88-91]. In addition, anti-ALK immunoreactivity has been observed in tissue immunostaining studies of other malignancies, such as breast carcinoma, malignant peripheral nerve-sheath tumors, and lipogenic tumors [70,89,91-93]; in these tumors, however, whether the full-length or rather fusion forms of ALK might be expressed in immuno positive cases has not yet been unequivocally determined (indeed, it has been noted that at least some breast carcinomas appear to exhibit an ALK immunostaining pattern more characteristic of certain ALK fusion proteins than the full-length receptor) [92]. With the exception of neuroblastoma (in which a pathogenic role for full-length ALK expression seems clear, vide infra ), the pathogenic significance – if any – of ALK receptor expression in each of the aforementioned tumor types remains uncertain at this time.…”