title: Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti-hormone therapy and reduced patient survival.
abstract: The AP-2gamma transcription factor encoded by the TFAP2C gene is a member of a family of homologous DNA binding proteins that play essential roles during vertebrate embryogenesis but show a restricted pattern of expression in the adult. Elevated expression of the AP-2alpha and AP-2gamma family members has been associated with a number of neoplasms, particularly breast cancer. Here we present an exploratory immunohistochemical study of an archival primary breast tumour series (n = 75) with parallel clinicopathological data using a new, well-characterized antibody to AP-2gamma. Heterogeneous, exclusively nuclear expression of AP-2gamma was found in the epithelial and myoepithelial compartments of normal breast and within tumour epithelial cells. In the breast cancer series, the most notable association was a correlation between elevated levels of AP-2gamma and shortened patient survival (p = 0.0009*). This relationship was also conserved in ER-positive and ErbB2-negative patients; sub-groups generally considered to have a relatively good prognosis. When patient data for survival and duration of treatment response on anti-hormone therapy were examined by multivariate analysis, AP-2gamma was revealed in this study to be an independent predictor of outcome for both survival (p = 0.005) and response to anti-hormone therapy (p = 0.046). Studies using in vitro models confirmed that while tamoxifen response is associated with lower levels of AP-2gamma, acquisition of resistance to this and other anti-hormone measures (eg faslodex or oestrogen deprivation) is associated with high levels of nuclear AP-2gamma. Together these data suggest that elevated tumour AP-2gamma expression can contribute to the failure of cells to growth arrest following anti-hormone treatment and lead to sustained growth and poorer patient outcome.
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: J M W
authors.initials: JM
authors.lastname: Gee
authors.forename: J J
authors.initials: JJ
authors.lastname: Eloranta
authors.forename: J C
authors.initials: JC
authors.lastname: Ibbitt
authors.forename: J F R
authors.initials: JF
authors.lastname: Robertson
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.forename: T
authors.initials: T
authors.lastname: Williams
authors.forename: R I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: H C
authors.initials: HC
authors.lastname: Hurst
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D050656:Transcription Factor AP-2 / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D013629:Tamoxifen