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The HCCR Oncoprotein as a Biomarker for Human Breast Cancer

Authors' Affiliations: ¹ Department of Surgery, ² Molecular Genetic Laboratory, ³ Department of Biostatistics, ⁴ Department of Clinical Pathology, and ⁵ Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea; ⁶ School of Life Sciences and Biotechnology, Korea University, Seoul, Korea ⁷ KeyGene Life Science Institute, KeyGene Science Corp., Ansan, Korea; and ⁸ School of Pharmacy, University of Maryland, Baltimore, Maryland

Requests for reprints: Jin Woo Kim, Molecular Genetic Laboratory, Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-040, Korea. Phone: 82-2-590-2389; Fax: 82-2-593-2389; E-mail: jinwoo{at}catholic.ac.kr.

Purpose: HCCR oncoprotein is reported to be related to tumorigenesis, including breast cancer, functioning as a negative regulator of p53. Mice transgenic for HCCR developed breast cancers. The objective of this study was to validate the HCCR oncoprotein as a candidate biomarker for breast cancer.

Experimental Design: HCCR expression in breast cancer cells was analyzed by quantitative PCR, ELISA, immunohistochemistry, Western blotting, fluorescence-activated cell sorting, and confocal microscopy. Epitope areas were determined using mass spectrometry through the analysis of time-dependent tryptic fragment patterns of HCCR. HCCR expression profiles in breast cancer patient sera were analyzed, and correlations with clinicopathologic data and carbohydrate antigen 15-3 (CA15-3) levels were determined.

Results: HCCR was up-regulated in breast cancer cells and tissues. The epitope regions of HCCR recognized by monoclonal antibody (BCS-1) were HFWTPK and QQTDFLDIYHAFR. According to fluorescence-activated cell sorting and confocal microscopic analysis, BCS-1 was bound to HCCR antigen on the cell surface. Serum HCCR concentrations were measured using ELISA from 299 subjects, including 129 patients with breast cancer, 24 patients with benign breast disease, and 158 normal volunteers, and comparisons were made to CA15-3. Serologic studies revealed an 86.8% sensitivity for HCCR in breast cancer, which was higher than 21.0% for CA15-3. Eighty-six of 98 (87.8%) patients with breast cancers that were negative for CA15-3 were positive for HCCR-1. A positive response rate of 83.3% was identified even at early stages for pathologic factors in breast cancer.

Conclusions: The HCCR assay has an advantage over CA15-3 in diagnosing breast cancer and detecting early stages of the disease.