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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.