Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

Abstract

Pleiotrophin (PTN, Ptn) is an 18kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTPbeta/zeta signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the ;;dotted" pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPbeta/zeta signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.

Figure 1. Expression of ALK in different human breast cancers

Low level magnification (×100). A. Infiltrating ductal carcinoma B. Infiltrating ductal carcinoma (papillary pattern). C. Infiltrating lobular carcinoma. D. Mucinous adenocarcinoma. E. Intraductal carcinoma. F. Medullary carcinoma. G. Paget’s disease. H. Normal breast tissue. Bar = 250 μm.

Figure 2. Different patterns of ALK expression in human breast cancers

A. “Dot-like” expression (arrows) pattern of ALK in an infiltrating ductal carcinoma. B. Mixed nuclear and cytoplasmic expression pattern of ALK in an infiltrating lobular carcinoma (arrows point high level expression of ALK in nuclei). C. Cytoplasmic expression pattern of ALK in an infiltrating ductal carcinoma (papillary subtype). D. Cytoplasmic expression pattern of ALK in a medullary carcinoma with low to moderate levels of expression of ALK in the nuclei. E. “Dot-like” expression (arrows) pattern of ALK in a comedocarcinoma. F. Mixed nuclear and cytoplasmic expression pattern of ALK in an intraductal carcinoma (arrows point high levels of expression of ALK in the nuclei). G. Mixed nuclear and cytoplasmic expression pattern of ALK in a mucinous adenocarcinoma. H. ALK expression in Paget’s disease of the breast localized in the cytoplasm and nuclei of fibroblasts and in the cytoplasm of epithelial cells. Bar = 20 μm.

Figure 3. Levels of expression of ALK 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% infiltrating duct carcinomas, 50% infiltrating lobular carcinomas, 50% medullary carcinomas, 100% mucinous carcinomas, 50% intraductal carcinomas, and 100% of the cases of Paget’s disease express high levels of ALK.