The receptor protein tyrosine phosphatase (RPTP)beta/zeta 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 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.

Figure 1. Expression of RPTPβ/ζ in different human breast cancers

A. Infiltrating ductal carcinoma. B. Normal breast tissue. C. Infiltrating lobular carcinoma. D. Infiltrating ductal carcinoma (papillary pattern). E. Medullary carcinoma. F. Mucinous adenocarcinoma. G. Intraductal carcinoma. H. Paget’s disease.

Figure 2. Levels of expression of RPTPβ/ζ in different human breast cancers

The levels of expression of ALK were quantified using light microscopy and scored in a scale from 1 to 3. The results demonstrated that 75% of the infiltrating ductal carcinomas and 75% of the infiltrating lobular carcinomas expressed low levels of RPTPβ/ζ whereas 100% of the medullary carcinomas, 100% of the mucinous carcinomas, and 100% of the intraductal carcinomas express moderate levels of RPTPβ/ζ. Interestingly, 80% of the cases of Paget’s disease were found to express high levels of ALK and the single sample of comedocarcinoma only weakly expressed RPTPβ/ζ.

Figure 3. Levels and pattern of expression of RPTPβ/ζ in infiltrating ductal carcinomas

Immunohistochemistry for RPTPβ/ζ in grade I (top panels), grade II (middle panels), and grade III (bottom panels). Nuclear staining was observed in all grades whereas the cytoplasmic expression was lost in the highest grade. Magnification: ×20 on the left panels, ×40 on the right panels.

Figure 4. Patterns of expression of RPTPβ/ζ in different carcinomas

A, unequal cytoplasmic and nuclear staining in an uncommon variant of apocrine carcinoma associated to androgen receptors. B, nuclear and cytoplasmic staining in a mucinous carcinoma. Magnification: ×40.