Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis

BMC Cancer

Research Article

Lawrence I Grossman¹  Matthew Burke²  Jingsheng Dong³  Marie-Claire Maroun³  Félix Fernández Madrid⁴  Richard Zarbo⁵  Dhananjay Chitale⁵  Michael Long⁶  Azadeh Stark⁷  Rocío Zeballos-Chávez⁸  S David Nathanson⁹  Carol Peebles^1,10  Walter Binder^1,10  Ofelia A Olivero^1,11 

[1] Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 East Canfield, 48201, Detroit, MI, USA;Department of Diagnostic Radiology, Henry Ford Hospital and Health Network, 2799 West Grand Blvd, 48202, Detroit, MI, USA;Department of Internal Medicine- Division of Rheumatology, Wayne State University School of Medicine, 640 Canfield, 48201, Detroit, MI, USA;Department of Internal Medicine- Division of Rheumatology, Wayne State University School of Medicine, 640 Canfield, 48201, Detroit, MI, USA;Karmanos Cancer Institute, 4100 John R Street, 48201, Detroit, MI, USA;Department of Pathology and Laboratory Medicine, Henry Ford Hospital, 2799 West Grand Blvd, 48202, Detroit, MI, USA;Department of Pathology, Children’s Hospital of Michigan, Wayne State School of Medicine, 48201, Detroit, MI, USA;Department of Pathology, Henry Ford Health System, 48202, Detroit, MI, USA;Center for Clinical Epidemiology & Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;Department of Pediatrics, Children’s Hospital of Michigan, Wayne State School of Medicine, Detroit, MI, USA;Department of Surgery, Henry Ford Health System, 2799 West Grand Boulevard, 48202, Detroit, MI, USA;INOVA Diagnostics Inc, 9900 Old Grove Rd, 92131, San Diego, CA, USA;National Cancer Institute, NIH, Laboratory of Cancer Biology and Genetics, 37 Convent Dr. MSC 4255, Bldg 37 Rm 4032, 20892-4255, Bethesda, MD, USA;

关键词: Autoantibodies;    Autoimmunity;    Immunogenicity;    Breast cancer;    Carcinogenesis;    Centrosomes;    Mitochondria;    Centromeres;    Cytoskeleton;   

DOI  :  10.1186/s12885-015-1385-8

 received in 2014-11-11, accepted in 2015-04-28,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe objective of this work was to demonstrate that autoantibodies in breast cancer sera are not epiphenomena, and exhibit unique immunologic features resembling the rheumatic autoimmune diseases.MethodsWe performed a comprehensive study of autoantibodies on a collection of sera from women with breast cancer or benign breast disease, undergoing annual screening mammography. All women in this study had suspicious mammography assessment and underwent a breast biopsy. We used indirect immunofluorescence, the crithidia assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens.ResultsAutoantibodies were detected in virtually all patients with breast cancer, predominantly of the IgG1 and IgG3 isotypes. The profile detected in breast cancer sera showed distinctive features, such as antibodies targeting mitochondria, centrosomes, centromeres, nucleoli, cytoskeleton, and multiple nuclear dots. The majority of sera showing anti-mitochondrial antibodies did not react with the M2 component of pyruvate dehydrogenase, characteristic of primary biliary cirrhosis. Anti-centromere antibodies were mainly anti-CENP-B. ELISAs for extractable nuclear antigens and the assays for dsDNA were negative.ConclusionsThe distinctive autoantibody profile detected in BC sera is the expression of tumor immunogenicity. Although some of these features resemble those in the rheumatic autoimmune diseases and primary biliary cirrhosis, the data suggest the involvement of an entirely different set of epithelial antigens in breast cancer. High titer autoantibodies targeting centrosomes, centromeres, and mitochondria were detected in a small group of healthy women with suspicious mammography assessment and no cancer by biopsy; this suggests that the process triggering autoantibody formation starts in the pre-malignant phase and that future studies using validated autoantibody panels may allow detection of breast cancer risk in asymptomatic women.Autoantibodies developing in breast cancer are not epiphenomena, but likely reflect an antigen-driven autoimmune response triggered by epitopes developing in the mammary gland during breast carcinogenesis. Our results support the validity of the multiple studies reporting association of autoantibodies with breast cancer. Results further suggest significant promise for the development of panels of breast cancer-specific, premalignant-phase autoantibodies, as well as studies on the autoantibody response to tumor associated antigens in the pathogenesis of cancer.

【 授权许可】

CC BY   
© Fernández Madrid et al. 2015