title: Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer.
abstract: The antiestrogen tamoxifen is a well-tolerated, effective treatment for estrogen receptor-α-positive (ER+) breast cancer, but development of resistance eventually limits its use. Here we show that expression of MAGEA2, and related members of this cancer-testis antigen family, is upregulated in tamoxifen-resistant tumor cells. Expression of MAGEA2 in tumor lines grown in vitro or as xenografts led to continued proliferation in the presence of tamoxifen. At the molecular level, we demonstrate that MAGEA2 protein localizes to the nucleus and forms complexes with p53 and ERα, resulting in repression of the p53 pathway but increased ER-dependent signaling. In a series of ER+, tamoxifen-treated breast cancer patients, we show a highly significant (P=0.006) association between MAGEA (melanoma-associated antigen) expression and reduced overall survival, confirming the clinical significance of our observations.
authors.affiliation: Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: P-P
authors.initials: PP
authors.lastname: Wong
authors.affiliation: Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: C C
authors.initials: CC
authors.lastname: Yeoh
authors.affiliation: Center for Epidemiology Mathematics and Statistics, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Ahmad
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Breast Pathology Research Group, Guy's Hospital, King's College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Gillett
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: V
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Jones
authors.affiliation: Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Hurst
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D058950:Melanoma-Specific Antigens / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D013629:Tamoxifen / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C574803:MageA2 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen