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Cancer Sci. 2003 Oct;94(10):864-70.

Ubiquitin-immunoreactive degradation products of cytokeratin 8/18 correlate with aggressive breast cancer.

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1
Department of Pathology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.

Abstract

Decreased amounts of cytokeratin (CK) 8/18 in the cytoplasm of breast cancer cells correlate with a poor prognosis. Although such decreases have been attributed to suppressed gene expression, accelerated protein degradation may also be responsible. In order to investigate whether selective degradation via the ubiquitin (Ub)-dependent proteasome pathway occurs in breast cancer, one- and two-dimensional (1-D and 2-D) immunoblot analysis was performed on cancerous and normal breast tissue from 50 breast cancer patients using the anti-Ub monoclonal antibodies (mAbs) KM691 and KM690. On 1-D gel electrophoresis, one broad band or two bands were detected at about 43 kDa; these were detected only in cancer tissue. Immunoreactive bands at 43 kDa were significantly associated with aggressive morphology (P = 0.011), nuclear p53 accumulation (P = 0.015) and overexpression of Her2 / neu protein (P = 0.012). On 2-D gel electrophoresis, these bands were fractionated into a group of several spots that formed a staircase pattern at 40-45 kDa. Partial amino acid sequencing analysis demonstrated that these Ub-immunoreactive spots corresponded to CK8 and CK18; however, since they did not have an amino-terminal domain, and were located at lower molecular weight positions than intact CK8 and CK18 on the 2-D gel, they were regarded as degradation products. CK18 degradation was confirmed by confocal microscopy as loss of the frame-like network that forms the luminal structure. These results indicate that CK 8/18 degradation products are detected specifically in breast cancer and may determine its aggressiveness.

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