Mining the pre-diagnostic antibody repertoire of TgMMTV-neu mice to identify autoantibodies useful for the early detection of human breast cancer

Journal of Translational Medicine

Mary L Disis²  Sam M Hanash³  Sasha E Stanton²  Elizabeth Broussard²  Yushe Dang²  Hailing Lu²  Jennifer S Childs²  Edmond Marzbani²  Melissa M Johnson¹  Lauren Rastetter²  Ekram Gad²  Jon Ladd¹  Jianning Mao² 

[1] Fred Hutchinson Cancer Research Center, Public Health Science, Arnold Building, M1-B208, PO Box 19024, Seattle, WA 98109, USA;Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA;Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Street, Unit Number: 1013, Houston, TX 77030, USA

关键词: Transgenic mice;    Autoantibodies;    Breast cancer;    Cancer diagnostics;   

Others  :  814040
DOI  :  10.1186/1479-5876-12-121

 received in 2013-10-29, accepted in 2014-04-28,  发布年份 2014

【 摘 要 】

Background

The use of autoantibodies for the early detection of breast cancer has generated much interest as antibodies can be readily assayed in serum when antigen levels are low. Ideally, diagnostic autoantibodies would be identified in individuals who harbored pre-invasive disease/high risk lesions leading to malignancy. Prospectively collected human serum samples from these individuals are rare and not often available for biomarker discovery. We questioned whether transgenic animals could be used to identify cancer-associated autoantibodies present at the earliest stages of the malignant transformation of breast cancer.

Methods

We collected sera from transgenic mice (TgMMTV-neu) from the time of birth to death by spontaneous mammary tumors. Using sera from a time point prior to the development of tumor, i.e. “pre-diagnostic”, we probed cDNA libraries derived from syngeneic tumors to identify proteins recognized by IgG antibodies. Once antigens were identified, selected proteins were evaluated via protein arrays, for autoantibody responses using plasma from women obtained prior to the development of breast cancer and matched controls. The ability of the antigens to discriminate cases from controls was assessed using receiver-operating-characteristic curve analyses and estimates of the area under the curve.

Results

We identified 6 autoantibodies that were present in mice prior to the development of mammary cancer: Pdhx, Otud6b, Stk39, Zpf238, Lgals8, and Vps35. In rodent validation cohorts, detecting both IgM and IgG antibody responses against a subset of the identified proteins could discriminate pre-diagnostic sera from non-transgenic control sera with an AUC of 0.924. IgG and IgM autoantibodies, specific for a subset of the identified antigens, could discriminate the samples of women who eventually developed breast cancer from case-matched controls who did not develop disease. The discriminatory potential of the pre-diagnostic autoantibodies was enhanced if plasma samples were collected greater than 5 months prior to a breast cancer diagnosis (AUC 0.68; CI 0.565-0.787, p = 0.0025).

Conclusion

Genetically engineered mouse models of cancer may provide a facile discovery tool for identifying autoantibodies useful for human cancer diagnostics.

【 授权许可】

   
2014 Mao et al.; licensee BioMed Central Ltd.

【 图 表 】

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