Abstract
Recent reports demonstrate that the expression of protein kinase C alpha (PKCα) in triple-negative breast cancer (TNBC) correlates with decreased survival outcomes. However, off-target effects of targeting PKCα and limited understanding of the signaling mechanisms upstream of PKCα 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 PKCα 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 PKCα promoter. Blocking the formation of the heterodimer by transfection of MZF-160–72 or Elk-1145–157 peptide fragments at the MZF-1 / Elk-1 interface decreases DNA-binding activity of the MZF-1 / Elk-1 complex at the PKCα promoter. Subsequently, PKCα expression, migration, tumorigenicity, and the epithelial–mesenchymal transition potential of TNBC cells decrease. These subsequent effects are reversed by transfection with full-length PKCα, confirming that the MZF-1/Elk-1 heterodimer is a mediator of PKCα in TNBC cells. These data suggest that the next therapeutic strategy in treating PKCα-related cancer will be developed from blocking MZF-1/Elk-1 interaction through their binding domain.
Highlights
Triple-negative breast cancers (TNBCs) comprise most of breast cancer phenotypes that are difficult to treat because they do not express estrogen receptor (ER), progesterone receptor (PR), and HER2 genes [1]
To determine whether the clinical relevance of the correlation between PKCα and Ets-like protein-1 (Elk-1) and/or myeloid zinc finger 1 (MZF-1) exists in breast cancer, we examined the expression of these proteins in tissue arrays by immunohistochemical (IHC) staining
We evaluated PKCαpromoter containing a putative binding site for MZF-1/Elk-1 via luciferase reporter assay in TNBC MDA-MB-231/Hs578T cells (Figure 1D), which showed more than one fold increase in the transcriptional activities by Elk-1 or/and MZF-1, supporting the role of Elk-1/ MZF-1 in regulating PKCα expression in TNBC
Summary
Triple-negative breast cancers (TNBCs) comprise most of breast cancer phenotypes that are difficult to treat because they do not express estrogen receptor (ER), progesterone receptor (PR), and HER2 genes [1]. Treatment for TNBC currently involves conventional chemotherapy; relapse leading to poor outcome occurs frequently because of high rates of metastasis and general inaccuracy of chemotherapy [2, 3]. Tam et al [9] showed that protein kinase C alpha (PKCα) is a central regulatory node in cells with EMTcaused breast CSCs. Hsu et al [10] revealed that PKCα is associated with TNBC/BTICs in both cell lines and tumor samples; the expression of PKCα in TNBC is correlated with decreased survival outcomes. Hsu et al [10] revealed that PKCα is associated with TNBC/BTICs in both cell lines and tumor samples; the expression of PKCα in TNBC is correlated with decreased survival outcomes These findings suggest that PKCα is a unique prognostic marker and an achievable therapeutic target for TNBC.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
