Abstract
We examined the feasibility of using a panel of autoantibodies to multiple tumor-associated proteins as a method for early detection of breast cancer and, more particularly, carcinoma in situ (CIS). PPIA, PRDX2, and FKBP52 were identified as early-stage breast cancer autoantigens by proteomic approaches. The seroreactivity of a panel of antibodies consisting of these three antigens and two previously described autoantigens, HSP60 and MUC1, was tested on 235 samples (60 from primary breast cancer patients, 82 from CIS patients, and 93 from healthy controls) with the use of specific ELISAs. FKBP52, PPIA, and PRDX2 mRNA and protein expression levels were evaluated by reverse transcription-PCR and immunohistochemistry in early-stage breast tumors. Three of five autoantibodies, FKBP52, PPIA, and PRDX2, showed significantly increased reactivity in primary breast cancer and CIS compared with healthy controls. When combined, the five markers significantly discriminated primary breast cancer [receiver operating characteristic area under the curve, 0.73; 95% confidence interval (95% CI), 0.60-0.79] and CIS (receiver operating characteristic area under the curve, 0.80; 95% CI, 0.71-0.85) from healthy individuals. Importantly, the receiver operating characteristic-area under the curve value of the autoantibody panel was able to distinguish CIS, including high grades, from healthy controls in women under the age of 50 years (receiver operating characteristic area under the curve, 0.85; 95% CI, 0.61-0.92). Finally, only FKBP52 mRNA and protein levels were found to be increased in CIS and primary breast cancer compared with healthy breast tissue. This autoantibody assay against a panel of five antigens allows for an accurate discrimination between early-stage breast cancer, especially CIS, and healthy individuals. These results could be of interest in detecting early breast cancer as an aid to mammography, especially in women under the age of 50 years with aggressive cancers.
Highlights
The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, for carcinoma in situ (CIS) and early-stage breast cancer
Because autoantibody reactivity against heat shock protein 60 (HSP60) and Mucin 1 (MUC1) were associated with the overexpression of the corresponding proteins in breast cancer compared with healthy breast tissue, we examined the expression levels of FKBP52, PPIA, and PRDX2 by real-time quantitative PCR on 29 early breast tumors and 29 healthy breast tissue samples
We report here a proteomics-based analysis to identify proteins that elicit a humoral response in early-stage breast cancers, including CIS
Summary
The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, for carcinoma in situ (CIS) and early-stage breast cancer. This study shows the clinical relevance of a combination of five antigens, identified by proteomic approach and validated in an independent cohort of 235 samples by ELISA, as a blood-screening test for early breast cancer detection. Of these five antigens, FKBP52 was found up-regulated in early-stage breast cancer, and its expression levels were correlated with cancer progression. Because mammographic screening declines in cohorts of patients with dense breast tissue and small lesions, as well as in premenopausal women, obtaining the status of this biomarker panel may guide the detection of early-stage cancer in women under the age of 50 years. Among the proteins of this panel, FKBP52 shows increased expression levels during breast cancer progression and thereby represents a potential immunotherapeutic target of early-stage breast cancer
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