Abstract 2683: Identification of tumor antigens in neu transgenic mice as diagnostic targets for the early detection of human breast cancer

Abstract

Abstract Tumor antigens, expressed early in disease, which can induce specific antibody response could serve as biomarkers for early detection of human breast cancer. However, the ability to obtain sera from women prior to the development of breast cancer is limited, which makes it difficult to identify early antigens directly from breast cancer patients. Transgenic mouse models have been proved to demonstrate similar antigen repertoire to breast cancer patients. Therefore, we propose to identify early tumor antigens in neu transgenic mice and use them as diagnostic targets for early detection of human breast cancer. We have collected serial sera from neu transgenic mice, sera collected before the animals develop palpable tumor “pre-diagnostic sera”. With serological analysis of recombinant cDNA expression libraries (SEREX) approach, we were able to identify nine tumor antigens from pre-diagnostic sera, Rpl5, TNFaip3/A20, Pdhx, Otud6b, Stk39, Zfp238, Dnajc10, Lgals8 and Vps35. These antigens demonstrated detectable IgG antibody response prior to tumor development in neu transgenic mice. IgM is the first antibody to be produced during a humoral immune response, so we questioned whether including antigen specific IgM with IgG responses could achieve a better diagnostic performance. Firstly, we analyzed receiver-operating-characteristic (ROC) curves of these antigens by IgG and IgM ELISA analysis in neu transgenic mice and 26 FVB control mice. By combining IgG and IgM ELISA, we were able to achieve a higher AUC: Otud6b and Stk39 show an AUC of 0.882, and adding Lgals8 IgG ELISA to this panel can achieve an AUC of 0.924 in discriminating cases from control mice. We documented that these autoantibodies are also detectable in the serum of women with breast cancer and then screened a panel of sera derived from the Women's Health Initiative cohort (samples obtained 6-18 months prior to the development of breast cancer) and case matched controls. We evaluated serum for the presence of IgG and IgM specific autoantibodies to Pdhx, Otud6b, and Stk39. With both IgG and IgM ELISA analysis, a panel combining the three antigens demonstrates an AUC of 0.633 in patients diagnosed within 5 month and an AUC of 0.688 in patients diagnosed within 5-18 month of the blood draw. In summary, we conclude that tumor antigens identified in neu transgenic mouse model can be used for early detection and diagnosis of breast cancer in women. The combination of antigen specific IgG and IgM antibodies may enhance the sensitivity of the assay for early detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2683. doi:10.1158/1538-7445.AM2011-2683