title: Proteomic profiling of triple-negative breast carcinomas in combination with a three-tier orthogonal technology approach identifies Mage-A4 as potential therapeutic target in estrogen receptor negative breast cancer.
abstract: Breast cancer is a very heterogeneous disease, encompassing several intrinsic subtypes with various morphological and molecular features, natural history and response to therapy. Currently, molecular targeted therapies are available for estrogen receptor (ER)(-) and human epidermal growth factor receptor 2 (Her2)-positive breast tumors. However, a significant proportion of primary breast cancers are negative for ER, progesterone receptor (PgR), and Her2, comprising the triple negative breast cancer (TNBC) group. Women with TNBC have a poor prognosis because of the aggressive nature of these tumors and current lack of suitable targeted therapies. As a consequence, the identification of novel relevant protein targets for this group of patients is of great importance. Using a systematic two dimensional (2D) gel-based proteomic profiling strategy, applied to the analysis of fresh TNBC tissue biopsies, in combination with a three-tier orthogonal technology (two dimensional PAGE/silver staining coupled with MS, two dimensional Western blotting, and immunohistochemistry) approach, we aimed to identify targetable protein markers that were present in a significant fraction of samples and that could define therapy-amenable sub-groups of TNBCs. We present here our results, including a large cumulative database of proteins based on the analysis of 78 TNBCs, and the identification and validation of one specific protein, Mage-A4, which was expressed in a significant fraction of TNBC and Her2-positive/ER negative lesions. The high level expression of Mage-A4 in the tumors studied allowed the detection of the protein in the tumor interstitial fluids as well as in sera. The existence of immunotherapeutics approaches specifically targeting this protein, or Mage-A protein family members, and the fact that we were able to detect its presence in serum suggest novel management options for TNBC and human epidermal growth factor receptor 2 positive/estrogen receptor negative patients bearing Mage-A4 positive tumors.
authors.affiliation: Department of Proteomics in Cancer, Institute of Cancer Biology, Danish Cancer Society, DK-2100, Copenhagen, Denmark.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabezón
authors.forename: Irina
authors.initials: I
authors.lastname: Gromova
authors.forename: Pavel
authors.initials: P
authors.lastname: Gromov
authors.forename: Reza
authors.initials: R
authors.lastname: Serizawa
authors.forename: Vera
authors.initials: V
authors.lastname: Timmermans Wielenga
authors.forename: Niels
authors.initials: N
authors.lastname: Kroman
authors.forename: Julio E
authors.initials: JE
authors.lastname: Celis
authors.forename: José M A
authors.initials: JM
authors.lastname: Moreira
mesh_terms: D000951:Antigens, Neoplasm / Q000097:blood* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D013058:Mass Spectrometry; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics; D011980:Receptors, Progesterone / Q000172:deficiency / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D020543:Proteome; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C095204:MAGEA4 protein, human; C508053:ERBB2 protein, human