A TFAP2C gene signature is predictive of outcome in HER2-positive breast cancer

Vincent T. Wu, Boris Kiriazov, Kelsey E. Koch, Vivian W. Gu, Anna C. Beck, Nicholas Borcherding, Tiandao Li, Peter Addo, Zachary J. Wehrspan, Weizhou Zhang, Terry A. Braun, Bartley J. Brown, Vimla Band, Hamid Band, Mikhail V. Kulak, Ronald J. Weigel

Research output: Contribution to journalArticle

Abstract

The AP-2γ transcription factor, encoded by the TFAP2C 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 TFAP2C 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. ComparingHER2+ 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-2γ and that contributed to growth and invasiveness. Pathway analysis implicated the MAPK13/p38d 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 theMAPK or retinoic acid pathways.

Original languageEnglish (US)
Pages (from-to)46-56
Number of pages11
JournalMolecular Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Wu, V. T., Kiriazov, B., Koch, K. E., Gu, V. W., Beck, A. C., Borcherding, N., Li, T., Addo, P., Wehrspan, Z. J., Zhang, W., Braun, T. A., Brown, B. J., Band, V., Band, H., Kulak, M. V., & Weigel, R. J. (2020). A TFAP2C gene signature is predictive of outcome in HER2-positive breast cancer. Molecular Cancer Research, 18(1), 46-56. https://doi.org/10.1158/1541-7786.MCR-19-0359