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

Margarite D Matossian; Van T Hoang; Hope E Burks; Jacqueline La; Steven Elliott; Courtney Brock; Douglas B Rusch; Aaron Buechlein; Kenneth P Nephew; Akshita Bhatt; Jane E Cavanaugh; Patrick T Flaherty; Bridgette M Collins-Burow; Matthew E Burow

doi:10.18632/oncoscience.535

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

Oncoscience. 2021 May 18:8:64-71. doi: 10.18632/oncoscience.535. eCollection 2021.

Authors

Margarite D Matossian^{1

2}, Van T Hoang^{1

2}, Hope E Burks^{1

2}, Jacqueline La^{1

2}, Steven Elliott¹, Courtney Brock¹, Douglas B Rusch³, Aaron Buechlein⁴, Kenneth P Nephew⁴, Akshita Bhatt⁵, Jane E Cavanaugh⁵, Patrick T Flaherty⁶, Bridgette M Collins-Burow^{1

7}, Matthew E Burow¹

Affiliations

¹ Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.
² These authors contributed equally to this work and are shared first authors.
³ Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN 47405, USA.
⁴ Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA.
⁵ Department of Pharmacology, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
⁶ Department of Medicinal Chemistry, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
⁷ Tulane Cancer Center, New Orleans, LA 70112, USA.

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.

Keywords: ERK5; MEK5; cell migration; epithelial to mesenchymal transition; triple negative breast cancer.

Abstract

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