Autoantibodies to Annexin XI-A and Other Autoantigens in the Diagnosis of Breast Cancer.

Department of Internal Medicine, Division of Rheumatology, Wayne Stste University, 4201 St. Antoine Boulevard, Detroit, MI 48201, USA. .
Cancer Research (Impact Factor: 9.33). 09/2004; 64(15):5089-96. DOI: 10.1158/0008-5472.CAN-03-0932
Source: PubMed


We report on the identification of autoantigens commonly recognized by sera from patients with breast cancer. We selected ten sera from patients with invasive ductal carcinoma (IDC) of the breast with high titer IgG autoantibodies for biopanning of a T7 phage breast cancer cDNA display library. A high throughput method involved the assembly of 938 T7 phages encoding potential breast cancer autoantigens. Microarrays of positive phages were probed with sera from 90 patients with breast cancer [15 patients with ductal carcinoma in situ (DCIS) and 75 patients with IDC of the breast], with 51 non-cancer control sera and with sera from 21 patients with systemic autoimmune diseases. A 12-phage breast cancer predictor group was constructed with phage inserts recognized by sera from patients with breast cancer and not by non-cancer or autoimmune control sera (P < 0.0001). Several autoantigens including annexin XI-A, the p80 subunit of the Ku antigen, ribosomal protein S6, and other unknown autoantigens could significantly discriminate between breast cancer and non-cancer control sera. Biopanning with three different sera led to the cloning of partial cDNA sequences identical to annexin XI-A. IgG autoantibodies reacting with the amino acid 41-74 sequence of annexin XI-A were found in 19% of all women with breast cancer but in 60% of sera from women with DCIS of the breast. In addition, partial sequences identical to annexin XI-A, nucleolar protein interacting with the forkhead-associated (FHA) domain of pKi-67, the KIAA1671 gene product, ribosomal protein S6, cyclin K, elongation factor-2, Grb2-associated protein 2, and other unknown proteins could distinguish DCIS from IDC of the breast and appear to be potential biomarkers for the diagnosis of breast cancer.

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    • "The SAS method allowed the identification of a panel of candidate tumor antigens in colorectal cancer [49]. Further, a robust approach combining phage display library derived from cancer tissue with protein microarray was proposed by Fernandez-Madrid et al. [50]. At first, a phage display cDNA library from breast cancer samples was screened against sera from 10 patients, then a microarray of the positive phages was probed with sera from another 90 patients. "
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    ABSTRACT: Since the advent of phage display technology, dating back to 1985, antibody libraries displayed on filamentous phage surfaces have been used to identify specific binders for many different purposes, including the recognition of tumors. Phage display represents a high-throughput technique for screening billions of random fusion antibodies against virtually any target on the surface or inside cancer cells, or even soluble markers found in patient serum. Many phage display derived binders targeting important tumor markers have been identified. Selection directed to tumoral cells' surfaces lead to the identification of unknown tumoral markers. Also the improvement of methods that require smaller amounts of cells has opened the possibility to use this approach on patient samples. Robust techniques combining an antibody library displayed on the phage surface and protein microarray allowed the identification of auto antibodies recognized by patient sera. Many Ab molecules directly or indirectly targeting angiogenesis have been identified, and one of them, ramucirumab, has been tested in 27 phase I-III clinical trials in a broad array of cancers. Examples of such antibodies will be discussed here with emphasis on those used as probes for molecular imaging and other clinical trials.
    International Journal of Molecular Sciences 12/2012; 13(5):5420-40. DOI:10.3390/ijms13055420 · 2.86 Impact Factor
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    • "Improvements to the SEREX approach have been made by the combination with solution-based phage-display technologies or by using eukaryotic expression systems (e.g. yeast, baculovirus system) (26), or by enlarging the repertoire of the cDNA expression library. "
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    ABSTRACT: In the process of tumorigenesis, normal cells are remodeled to cancer cells and protein expression patterns are changed to those of tumor cells. A newly formed tumor microenvironment elicits the immune system and, as a result, a humoral immune response takes place. Although the tumor antigens are undetectable in sera at the early stage of tumorigenesis, the nature of an antibody amplification response to antigens makes tumor-associated autoantibodies as promising early biomarkers in cancer diagnosis. Moreover, the recent development of proteomic techniques that make neo-epitopes of tumor-associated autoantigens discovered concomitantly has opened a new area of 'immuno-proteomics', which presents tumor-associated autoantibody signatures and confers information to redefine the process of tumorigenesis. In this article, the strategies recently used to identify and validate serum autoantibodies are outlined and tumor-associated antigens suggested until now as diagnostic/prognostic biomarkers in various tumor types are reviewed. Also, the meaning of autoantibody signatures and their clinical utility in personalized medicine are discussed. [BMB Reports 2012; 45(12): 677-685].
    BMB reports 12/2012; 45(12):677-85. DOI:10.5483/BMBRep.2012.45.12.236 · 2.60 Impact Factor
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    • "The corresponding tumour auto-antibodies could be used as biomarkers for early diagnosis and prognosis of cancer (Anderson & LaBaer 2005, Casiano et al. 2006, Sanchez-Carbayo 2006). Proteins like ANXA11, p53, HIP1 and ECPKA are known to serve as TAA biomarkers for various cancers (Bradley et al. 2005, Fernandez-Madrid et al. 2004, Nesterova et al. 2006, Soussi 2000). Tomaino et al. (2007) used Western blot analysis to identify autoantibodies against pancreatic ductal adenocarcinoma (PDAC) associated antigens from the PDAC sera. "
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    ABSTRACT: Aberrantly expressed proteins in tumours evoke an immunological response. These immunogenic proteins can serve as potential biomarkers for the early diagno-sis of cancers. In this study, we performed a candidate marker screen on macroarrays containing 38,016 hu-man proteins, derived from a human fetal-brain expres-sion library, with the pools of sera from breast cancer patients (1 pool of benign samples, 3 pools of ductal carcinoma and 2 pools of lobular carcinoma) and 1 pool of sera from healthy women. A panel of 642 sero-reactive clones were deduced from these macroarray experiments which include 284 in-frame clones. Over-representation analyses of the sero-reactive in-frame clones enabled the identification of the sets of genes over-expressed in various pathways of the functional categories (KEGG, Transpath, Pfam and GO). Protein microarrays, generated using the His-tag proteins de-rived from the macroarray experiments, were used to evaluate the sera from breast cancer patients (24 malig-nant, 16 benign) and 20 control individuals. Using the PAM algorithm we elucidated a panel of 50 clones which enabled the correct classification prediction of 93% of the breast-nodule positive group (benign & malignant) sera from healthy individuals' sera with 100% sensitivity and 85% specificity. This was fol-lowed by over-representation analysis of the signifi-cant clones derived from the class prediction.
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