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

• Published in: Molecular cancer research 2020-01, Vol.18 (1), p.46-56
• Main Authors: Wu, Vincent T, Kiriazov, Boris, Koch, Kelsey E, Gu, Vivian W, Beck, Anna C, Borcherding, Nicholas, Li, Tiandao, Addo, Peter, Wehrspan, Zachary J, Zhang, Weizhou, Braun, Terry A, Brown, Bartley J, Band, Vimla, Band, Hamid, Kulak, Mikhail V, Weigel, Ronald J
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-19-0359

The AP-2γ transcription factor, encoded by the gene, regulates the expression of estrogen receptor-alpha (ERα) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2γ in other breast cancer subtypes. A subset of HER2 breast cancers with amplification of the gene locus becomes addicted to AP-2γ. Herein, we sought to define AP-2γ gene targets in HER2 breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2γ. Comparing HER2 cell lines that demonstrated differential response to growth and invasiveness with knockdown of , we identified a set of 68 differentially expressed target genes. and were among the genes differentially regulated by AP-2γ and that contributed to growth and invasiveness. Pathway analysis implicated the /p38δ 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-2γ gene signature was found to be highly predictive of outcome in patients with HER2 breast cancer. We conclude that AP-2γ regulates a set of genes in HER2 breast cancer that drive cancer growth and invasiveness. The AP-2γ 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. IMPLICATIONS: A set of genes regulated by AP-2γ in HER2 breast cancer that drive proliferation and invasion were identified and provided a gene signature that is predictive of outcome in HER2 breast cancer.