Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

Abstract

The AP-2γ 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-2α and AP-2γ 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-2γ . Heterogeneous, exclusively nuclear expression of AP-2γ 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-2γ 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-2γ 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-2γ , acquisition of resistance to this and other anti-hormone measures (eg faslodex or oestrogen deprivation) is associated with high levels of nuclear AP-2γ . Together these data suggest that elevated tumour AP-2γ expression can contribute to the failure of cells to growth arrest following anti-hormone treatment and lead to sustained growth and poorer patient outcome.

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21 cip ( CDKN1A )

“…As with TFAP2C (13,16) and Myc (37), KDM5B overexpression has been associated with a poorer outcome in breast cancer patients (22), and all three proteins have been shown to promote cell proliferation by facilitating G 1 /S transition (36,39), a checkpoint particularly sensitive to cellular levels of p21 cip . Repression of CDKN1A, mediated by Myc or TFAP2C, has been documented previously (see the introduction), and the related KDM5A demethylase was shown to regulate H3K4 methylation status at this locus in gastric tumor cells, although its site and mode of binding transfected with nonsilencing control siRNA (nsRNAi) or siRNA against Myc (siMyc) or KDM5B (siKDM5B) or treated with doxycycline (Dox) to induce shTFAP2C and harvested 72 h later for use in ChIP with antibodies against IgG (control), TFAP2C, (KDM5B, or Myc.…”

“…However, expression of the TFAP2A and TFAP2C proteins has been demonstrated in a variety of solid tumors, including breast cancer and melanoma (reviewed in reference 24). TFAP2A expression in breast tumors has been associated with a favorable outcome and shows a positive correlation with expression of estrogen recepter ␣ (ER␣) and CDKN1A (14), while elevated expression of TFAP2C has generally been correlated with an adverse phenotype and resistance to hormone therapy (13,16). Studies in vitro have shown that direct AP-2 transcriptional targets include many genes involved in tumor progression.…”

Hallmarks of Aromatase Inhibitor Drug Resistance Revealed by Epigenetic Profiling in Breast Cancer

“…For ERa, TFAP2 and TCF4 motifs were selectively enriched for the poor outcome patients. AP-2 can directly guide ERa/ chromatin interactions (13), promotes breast cancer cell proliferation (37), and correlates with poor outcome (38). TCF4 enhances breast cancer cell invasion (39) and binds ERa (40), providing a level of cross-control between estradiol and wnt pathways (40).…”

TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma))

“…Prognosis Resistance to Tamoxifen treatment and reduction of survival rate had correlation with TFAP2C overexpression (Guler et al, 2007). ERBB2-negative/AP-2-positive expression patients had a better prognosis than patients with ERBB2-positive/AP-2-positive tumors (Gee et al, 2009). In primary breast cancer specimens, high TFAP2C and low CD44 expression were associated with pCR after neoadjuvant chemotherapy and could be predictive of tumors that have improved response to neoadjuvant chemotherapy (Spanheimer et al, 2013a).…”

“…TFAP2C silencing coincided with acquisition of an active chromatin conformation at the CDKN1A locus and increased gene expression (Gee et al, 2009). TFAP2C SUMOylation modification was described in mammalian cells and SUMO site was mapped to conserved lysine 10 (Eloranta and Hurst, 2002).…”