Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression.

The ability of the immune system to recognize structurally altered, amplified or aberrantly expressed proteins can be used to identify molecules of etiologic relevance to cancer and to define targets for cancer immunotherapy. In the current study, ninety-four distinct antigens reactive with serum IgG from breast cancer patients were identified by immunoscreening breast cancer-derived cDNA expression libraries (SEREX). A serological profile was generated for each antigen on the basis of reactivity with allogeneic sera from normal individuals and cancer patients, and mRNA expression profiles for coding sequences were assembled based upon the tissue distribution of expressed sequence tags, Northern blots and real-time RT-PCR. Forty antigens reacted exclusively with sera from cancer patients. These included well-characterized tumor antigens, e.g. MAGE-3, MAGE-6, NY-ESO-1, Her2neu and p53, as well as newly-defined breast cancer antigens, e.g. kinesin 2, TATA element modulatory factor 1, tumor protein D52 and MAGE D, and novel gene products, e.g. NY-BR-62, NY-BR-75, NY-BR-85, and NY-BR-96. With regard to expression profiles, two of the novel gene products, NY-BR-62 and NY-BR-85, were characterized by a high level of testicular mRNA expression, and were overexpressed in 60% and 90% of breast cancers, respectively. In addition, mRNA encoding tumor protein D52 was overexpressed in 60% of breast cancer specimens, while transcripts encoding SNT-1 signal adaptor protein were downregulated in 70% of these cases. This study adds to the growing list of breast cancer antigens defined by SEREX and to the ultimate objective of identifying the complete repertoire of immunogenic gene products in human cancer (the cancer immunome).

[1]  P. Coulie,et al.  The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas , 1993, The Journal of experimental medicine.

[2]  L. Michaux,et al.  LAGE‐1, a new gene with tumor specificity , 1998, International journal of cancer.

[3]  K. Itakura,et al.  Repression by a differentiation-specific factor of the human cytomegalovirus enhancer. , 1996, Nucleic acids research.

[4]  J. Renauld,et al.  A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas , 1994, The Journal of experimental medicine.

[5]  A. Dejean,et al.  SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia , 1997 .

[6]  M. Goldfarb,et al.  Broadly expressed SNT-like proteins link FGF receptor stimulation to activators of Ras. , 1996, Oncogene.

[7]  D. Jäger,et al.  Cancer-testis antigens and ING1 tumor suppressor gene product are breast cancer antigens: characterization of tissue-specific ING1 transcripts and a homologue gene. , 1999, Cancer research.

[8]  Yao-Tseng Chen,et al.  A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Wei Chen,et al.  Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. , 1994, Cancer research.

[10]  S. Rosenberg,et al.  A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames. , 1998, Journal of immunology.

[11]  M. Pfreundschuh,et al.  Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. Willis,et al.  Isolation, cDNA cloning, and overexpression of a 33-kD cell surface glycoprotein that binds to the globular "heads" of C1q , 1994, The Journal of experimental medicine.

[13]  L. Old,et al.  Cancer Tumor antigens. , 1997, Current opinion in immunology.

[14]  G Sybrecht,et al.  Role of amplified genes in the production of autoantibodies. , 1999, Blood.

[15]  Yao-Tseng Chen,et al.  Characterization of human colon cancer antigens recognized by autologous antibodies , 1998, International journal of cancer.

[16]  K. Datta,et al.  Molecular Cloning of Human Fibroblast Hyaluronic Acid-binding Protein Confirms Its Identity with P-32, a Protein Co-purified with Splicing Factor SF2 , 1996, The Journal of Biological Chemistry.

[17]  K. Alitalo,et al.  Vascular endothelial growth factor B, a novel growth factor for endothelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  David I. Smith,et al.  A novel region of deletion on chromosome 6q23.3 spanning less than 500 Kb in high grade invasive epithelial ovarian cancer , 1999, Oncogene.

[19]  G N Shah,et al.  Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Rosenberg,et al.  Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[21]  V. Brusic,et al.  Melan-A/MART-1(51-73) represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4(+) T cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Rosenberg,et al.  Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. , 1999, Science.

[23]  A. Dejean,et al.  SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  K. Winzer,et al.  A defined chromosome 6q fragment (at D6S310) harbors a putative tumor suppressor gene for breast cancer. , 1996, Oncogene.

[25]  J. Green,et al.  Isolation and characterization of a novel gene expressed in multiple cancers. , 1996, Oncogene.

[26]  S. Komiyama,et al.  Molecular cloning of a human cDNA encoding a novel protein, DAD1, whose defect causes apoptotic cell death in hamster BHK21 cells , 1993, Molecular and cellular biology.

[27]  M. Green,et al.  A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. , 1996, Genes & development.

[28]  I. Vernos,et al.  Xklp2, a Novel Xenopus Centrosomal Kinesin-like Protein Required for Centrosome Separation during Mitosis , 1996, Cell.

[29]  T. Soussi,et al.  p53 Antibodies in the sera of patients with various types of cancer: a review. , 2000, Cancer research.

[30]  Yao-Tseng Chen,et al.  Identification of multiple cancer/testis antigens by allogeneic antibody screening of a melanoma cell line library. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Chawnshang Chang,et al.  Isolation and Characterization of ARA160 as the First Androgen Receptor N-terminal-associated Coactivator in Human Prostate Cells* , 1999, The Journal of Biological Chemistry.

[32]  M. Pfreundschuh,et al.  Human neoplasms elicit multiple specific immune responses in the autologous host. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Yao-Tseng Chen,et al.  Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumor suppressor gene locus on chromosome 3p21.3. , 1998, Cancer research.

[34]  O. de Backer,et al.  A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma , 1995, The Journal of experimental medicine.

[35]  L. Gerace,et al.  Identification of novel M phase phosphoproteins by expression cloning. , 1996, Molecular biology of the cell.

[36]  P. Romero,et al.  Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes , 1994, The Journal of experimental medicine.

[37]  P. Yaciuk,et al.  Identification of a Novel SNF2/SWI2 Protein Family Member, SRCAP, Which Interacts with CREB-binding Protein* , 1999, The Journal of Biological Chemistry.

[38]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[39]  B. Olffson Vascular endothelial grouth facter B, a novel growth facter for endothelial cells , 1996 .

[40]  S. Naylor,et al.  Definition of a tumor suppressor locus within human chromosome 3p21-p22. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[41]  M. Probst-Kepper,et al.  A New Antigen Recognized by Cytolytic T Lymphocytes on a Human Kidney Tumor Results from Reverse Strand Transcription , 1999, The Journal of experimental medicine.

[42]  S. Rosenberg,et al.  Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Minna,et al.  Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene , 1998, Oncogene.

[44]  R. Brasseur,et al.  BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. , 1995, Immunity.

[45]  L. Pavlova,et al.  High resolution mapping of chromosome 6 deletions in cervical cancer. , 1999, Oncology reports.

[46]  P. Chomez,et al.  A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. , 1991, Science.

[47]  V. Brusic,et al.  Melan-A/MART-151–73 represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4+ T cells , 2000 .

[48]  P. Gunning,et al.  Identification of homo- and heteromeric interactions between members of the breast carcinoma-associated D52 protein family using the yeast two-hybrid system , 1998, Oncogene.

[49]  D. Thomson,et al.  Analysis of the anti-p53 antibody response in cancer patients. , 1993, Cancer research.

[50]  Lloyd J. Old,et al.  A Survey of the Humoral Immune Response of Cancer Patients to a Panel of Human Tumor Antigens , 1998, The Journal of experimental medicine.

[51]  F. Brasseur,et al.  A new MAGE gene with ubiquitous expression does not code for known MAGE antigens recognized by T cells. , 1999, Cancer research.

[52]  K. Kok,et al.  Major role for a 3p21 region and lack of involvement of the t(3;8) breakpoint region in the development of renal cell carcinoma suggested by loss of heterozygosity analysis. , 1995, Genes, chromosomes & cancer.

[53]  D. Jäger,et al.  Antigens recognized by autologous antibody in patients with renal‐cell carcinoma , 1999, International journal of cancer.

[54]  S. Rosenberg,et al.  Identification of a Novel Major Histocompatibility Complex Class II–restricted Tumor Antigen Resulting from a Chromosomal Rearrangement Recognized by CD4+ T Cells , 1999, The Journal of experimental medicine.