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Autoimmunity to the M_r 32,000 Subunit of Replication Protein A in Breast Cancer¹

Center for Molecular Medicine and Genetics [J. E. T., F. F-M.], Karmanos Cancer Institute [J. E. T., F. F-M.], Department of Internal Medicine, Division of Rheumatology [H. A., N. T., X. Y., P. V., J. L. G., F. F-M.], Division of Hematology/Oncology [M. J. K., J. F. E.], and Department of Pathology [J. B. V.], Wayne State University, Detroit, Michigan 48201, and Institute for Biomedical Research, Birmingham, Michigan 48304 [R. L. K.]

Purpose: We sought to identify autoantigens recognized by antibodies in breast cancer patient sera with potential diagnostic or prognostic significance.

Experimental Design: Serum from a female breast cancer patient exhibiting a high titer antinuclear antibody was used to screen a HeLa cDNA expression library, leading to the cloning of a cDNA for the M_r 32,000 subunit of replication protein A (RPA32). RPA32 expression and localization were assayed in autologous tumor by monoclonal antibody staining. A specific ELISA using recombinant protein was used to screen sera from 801 breast cancer patients and 65 controls.

Results: A relationship between anti-replication protein A (RPA) antibodies and the ductal breast carcinoma of the proband was suggested by overexpression and aberrant localization of RPA32 in tumor cells as compared with surrounding normal ductal tissue and by the presence of anti-RPA32 antibodies before the diagnosis. The prevalence of anti-RPA32 antibodies was significantly higher (P < 0.01) among breast cancer patients (87 of 801 patients) than among noncancer controls (0 of 65 controls). Similarly, anti-RPA32 antibodies were present in 4 of 39 patients with intraductal in situ carcinoma. No associations were found between anti-RPA antibodies and survival, occurrence of a second tumor, metastases, or antibodies to p53. Reactivity to RPA32 also was detected in sera from 3 of 47 patients with other cancers.

Conclusions: In view of the central role of RPA in DNA replication, recombination, and repair, we suggest that autoimmunity to RPA32 may reflect molecular changes involved in the process of tumorigenesis. The finding of antibodies to RPA32 before diagnosis and their prevalence in in situ carcinoma suggest that they are potentially useful markers of early disease.

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