Expression of the onconeural protein CDR1 in cerebellum and ovarian cancer.

Cecilie Totland,Torbjørn Kråkenes,Kibret Mazengia,Mette Haugen,Christian Vedeler

doi:10.18632/oncotarget.25252

Cecilie Totland, Torbjørn Kråkenes + Show 3 more

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https://doi.org/10.18632/oncotarget.25252

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Abstract

Cerebellar degeneration related protein 1 (CDR1) is expressed in the cerebellum, and CDR1 antibodies have been associated with paraneoplastic cerebellar degeneration (PCD). In this study, we examined CDR1 expression in cerebellum and in ovarian and breast tumors, as well as the intracellular localization of CDR1 in cancer cells in culture. CDR1 was strongly expressed in the cytosol and dendrites of Purkinje cells and in interneurons of the molecular layer in cerebellum. CDR1 was also present in ovarian and breast tumors, as well as in ovarian and breast cancer cell lines, but was not present in normal breast or ovarian tissue. In cells overexpressing CDR1, CDR1 localized close to the plasma membrane in a polarized pattern at one edge. CDR1 was strongly expressed on the outer surface, apparently in filopodias or lamellipodias, in cells endogenously expressing CDR1. Overexpression of CDR1 showed a 37 and a 45 kDa band in western blot. The 37-kDa isoform was present in 16 ovarian cancer lysates, while the 45-kDa isoform was only found in three ovarian cancer patients. The presence of CDR1 in ovarian cancer was not associated with PCD. CDR1 antibodies were only found in serum from one patient with PCD and ovarian tumor with metastases. Therefore, CDR1 is probably not a marker for PCD. However, CDR1 may be associated with cell migration and differentiation.

Highlights

Paraneoplastic neurological syndromes (PNS) are rare disorders associated with different forms of cancer, most commonly small-cell lung cancer, ovarian cancer and breast cancer
We found that Cerebellar degeneration related protein 1 (CDR1) is expressed in human, mouse and rat Purkinje cells, as well as in interneurons in the molecular layer
This is supported by BioGPS, which shows that CDR1 mRNA is highly expressed in cerebellum, but not in other normal tissue

Summary

Introduction

Paraneoplastic neurological syndromes (PNS) are rare disorders associated with different forms of cancer, most commonly small-cell lung cancer, ovarian cancer and breast cancer. Such tumors are more likely to overexpress onconeural proteins, and PNS occurs as an autoimmune response where autoantibodies and cytotoxic T-cells meant to target tumor antigens attack neurons expressing similar proteins [1, 2]. In 1986 it was reported that sera from patients with PCD and ovarian or breast cancer reacted with proteins of 62-64 kDa and 34-38 kDa [8]. The protein consists of 34 inexact repetitive hexapeptides with a core of the acidic amino acids glutamate (E) and aspartate (D) flanked by other amino acids [6] This repetitive pattern accounts for more than 50% of the human CDR1 sequence (www.uniprot.org, #P51861). The amino acid distribution gives CDR1 a polarized www.oncotarget.com composition with a negatively charged N-terminus and a positively charged C-terminus

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