MZF-1/Elk-1 interaction domain as therapeutic target for protein kinase Ca-based triple-negative breast cancer cells

Recent reports demonstrate that the expression of protein kinase C alpha (PKCa) in triple-negative breast cancer (TNBC) correlates with decreased survival outcomes. However, off-target effects of targeting PKCa and limited understanding of the signaling mechanisms upstream of PKCa have hampered previous efforts to manipulate this ubiquitous gene. This study shows that the expression of both myeloid zinc finger 1 (MZF-1) and Ets-like protein-1 (Elk-1) correlates with PKCa expression in TNBC. We found that the acidic domain of MZF-1 and the heparin-binding domain of Elk-1 facilitate the heterodimeric interaction between the two genes before the complex formation binds to the PKCa promoter. Blocking the formation of the heterodimer by transfection of MZF-1(60-72) or Elk-1(145-157) peptide fragments at the MZF-1 / Elk-1 interface decreases DNA-binding activity of the MZF-1 /Elk-1 complex at the PKCa promoter. Subsequently, PKCa expression, migration, tumorigenicity, and the epithelial-mesenchymal transition potential of TNBC cells decrease. These subsequent effects are reversed by transfection with full-length PKCa, confirming that the MZF-1/Elk-1 heterodimer is a mediator of PKCa in TNBC cells. These data suggest that the next therapeutic strategy in treating PKCa-related cancer will be developed from blocking MZF-1/Elk-1 interaction through their binding domain.