A TFAP2C Gene Signature Is Predictive of Outcome in HER2-Positive Breast Cancer

The AP-2 gamma transcription factor, encoded by the TFAP2C gene, regulates the expression of estrogen receptor-alpha (ER alpha) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2 gamma in other breast cancer subtypes. A subset of HER2(+) breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2 gamma. Herein, we sought to define AP-2 gamma gene targets in HER2(+) breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2 gamma. Comparing HER2(+) cell lines that demonstrated differential response to growth and invasiveness with knockdown of TFAP2C, we identified a set of 68 differentially expressed target genes. CDH5 and CDKN1A were among the genes differentially regulated by AP-2 gamma and that contributed to growth and invasiveness. Pathway analysis implicated the MAPK13/p38 delta and retinoic acid regulatory nodes, which were confirmed to display divergent responses in different HER2(+) cancer lines. To confirm the clinical relevance of the genes identified, the AP-2 gamma gene signature was found to be highly predictive of outcome in patients with HER2(+) breast cancer. We conclude that AP-2 gamma regulates a set of genes in HER2(+) breast cancer that drive cancer growth and invasiveness. The AP-2 gamma gene signature predicts outcome of patients with HER2(+) breast cancer and pathway analysis predicts that subsets of patients will respond to drugs that target the MAPK or retinoic acid pathways.