Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer
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https://doi.org/10.18632/oncoscience.535
Margarite D. Matossian1*, Van T. Hoang1*, Hope E. Burks1*, Jacqueline La1*, Steven Elliott1, Courtney Brock1, Douglas B. Rusch2, Aaron Buechlein3, Kenneth P. Nephew3, Akshita Bhatt4, Jane E. Cavanaugh4, Patrick T. Flaherty5, Bridgette M. Collins-Burow1,,6, Matthew E. Burow1
1Department of Medicine: Section of Hematology and Oncology, Tulane University, New Orleans LA
2Center for Genomics and Bioinformatics, Indiana University, Bloomington IN
3Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington IN
4Department of Pharmacology, Duquesne University School of Pharmacy, Pittsburgh, PA
5Department of Medicinal Chemistry, Duquesne University School of Pharmacy, Pittsburgh, PA
6Tulane Cancer Center, New Orleans, LA
*These authors contributed equally to this work and are shared first authors.
Correspondence to:
Matthew E. Burow, email: [email protected]
Keywords: triple negative breast cancer; MEK5; epithelial to mesenchymal transition; cell migration; ERK5
Received: December 13, 2020 Accepted: April 26, 2021 Published: May 18, 2021
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.
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