title: Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Autoantibodies 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Internal Medicine- Division of Rheumatology, Wayne State University School of Medicine, 640 Canfield, Detroit, MI, 48201, USA. fmadrid@med.wayne.edu.|Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA. fmadrid@med.wayne.edu.
authors.forename: Félix Fernández
authors.initials: FF
authors.lastname: Madrid
authors.affiliation: Department of Internal Medicine- Division of Rheumatology, Wayne State University School of Medicine, 640 Canfield, Detroit, MI, 48201, USA. mmaroun@med.wayne.edu.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Maroun
authors.affiliation: National Cancer Institute, NIH, Laboratory of Cancer Biology and Genetics, 37 Convent Dr. MSC 4255, Bldg 37 Rm 4032, Bethesda, MD, 20892-4255, USA. oliveroo@exchange.nih.gov.
authors.forename: Ofelia A
authors.initials: OA
authors.lastname: Olivero
authors.affiliation: Department of Pathology, Children's Hospital of Michigan, Wayne State School of Medicine, Detroit, MI, 48201, USA. plong@med.wayne.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Pathology, Henry Ford Health System, Detroit, MI, 48202, USA. ASTARK1@hfhs.org.|Center for Clinical Epidemiology & Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ASTARK1@hfhs.org.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Stark
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 East Canfield, Detroit, MI, 48201, USA. lgrossman@wayne.edu.
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Grossman
authors.affiliation: INOVA Diagnostics Inc, 9900 Old Grove Rd, San Diego, CA, 92131, USA. cpeebles@sd.inovadx.com.
authors.forename: Walter
authors.initials: W
authors.lastname: Binder
authors.affiliation: Department of Internal Medicine- Division of Rheumatology, Wayne State University School of Medicine, 640 Canfield, Detroit, MI, 48201, USA. jinsheng3@gmail.com.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Diagnostic Radiology, Henry Ford Hospital and Health Network, 2799 West Grand Blvd, Detroit, MI, 48202, USA. MBurke1@hfhs.org.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burke
authors.affiliation: Department of Surgery, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI, 48202, USA. Dnathan1@hfhs.org.
authors.forename: S David
authors.initials: SD
authors.lastname: Nathanson
authors.affiliation: Department of Pathology and Laboratory Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI, 48202, USA. rzarbo1@hfhs.org.
authors.forename: Richard
authors.initials: R
authors.lastname: Zarbo
authors.affiliation: Department of Pathology and Laboratory Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI, 48202, USA. dchital1@hfhs.org.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Chitale
authors.affiliation: Department of Pediatrics, Children's Hospital of Michigan, Wayne State School of Medicine, Detroit, MI, USA. plong@med.wayne.edu.
authors.forename: Rocío
authors.initials: R
authors.lastname: Zeballos-Chávez
authors.affiliation: INOVA Diagnostics Inc, 9900 Old Grove Rd, San Diego, CA, 92131, USA. cpeebles@sd.inovadx.com.
authors.forename: Carol
authors.initials: C
authors.lastname: Peebles
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood*; D034961:Antigens, Nuclear; D001941:Breast Diseases / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology*; D063646:Carcinogenesis / Q000276:immunology*; D002278:Carcinoma in Situ / Q000276:immunology*; D018270:Carcinoma, Ductal, Breast / Q000276:immunology*; D002466:Cell Nucleolus / Q000276:immunology; D002503:Centromere / Q000276:immunology; D051936:Centromere Protein B / Q000276:immunology; D018385:Centrosome / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D034961:Antigens, Nuclear; D051936:Centromere Protein B; D007074:Immunoglobulin G