Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer

DOI

10.18632/oncoscience.535

Authors

Margarite D. Matossian, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Van T. Hoang, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Hope E. Burks, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Jacqueline La, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Steven Elliott, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Courtney Brock, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Douglas B. Rusch, Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN 47405, USA.
Aaron Buechlein, Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA.
Kenneth P. Nephew, Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA.
Akshita Bhatt, Department of Pharmacology, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
Jane E. Cavanaugh, Department of Pharmacology, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
Patrick T. Flaherty, Department of Medicinal Chemistry, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
Bridgette M. Collins-Burow, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
Matthew E. Burow, Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.

Document Type

Journal Article

Publication Date

1-1-2021

Publication Title

Oncoscience

Volume

8

First Page

64

Last Page

71

ISSN

2331-4737

Keywords

ERK5, MEK5, cell migration, epithelial to mesenchymal transition, triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. A defining feature of TNBC is the propensity to metastasize and acquire resistance to cytotoxic agents. Mitogen activated protein kinase (MAPK) and extracellular regulated kinase (ERK) signaling pathways have integral roles in cancer development and progression. While MEK5/ERK5 signaling drives mesenchymal and migratory cell phenotypes in breast cancer, the specific mechanisms underlying these actions remain under-characterized. To elucidate the mechanisms through which MEK5 regulates the mesenchymal and migratory phenotype, we generated stably transfected constitutively active MEK5 (MEK5-ca) TNBC cells. Downstream signaling pathways and candidate targets of MEK5-ca cells were based on RNA sequencing and confirmed using qPCR and Western blot analyses. MEK5 activation drove a mesenchymal cell phenotype independent of cell proliferation effects. Transwell migration assays demonstrated MEK5 activation significantly increased breast cancer cell migration. In this study, we provide supporting evidence that MEK5 functions through FRA-1 to regulate the mesenchymal and migratory phenotype in TNBC.

Open Access

OA

Preprint

Additional Link

Repository Citation

Matossian, M. D., Hoang, V. T., Burks, H. E., La, J., Elliott, S., Brock, C., Rusch, D. B., Buechlein, A., Nephew, K. P., Bhatt, A., Cavanaugh, J. E., Flaherty, P. T., Collins-Burow, B. M., & Burow, M. E. (2021). Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer. Oncoscience, 8, 64-71. https://doi.org/10.18632/oncoscience.535