Details

Autor(en) / Beteiligte

• Monlish, Darlene Anne

Titel

Age-related effects on the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in breast cancer and the characterization of novel MEK5 inhibitors

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2013

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Age remains the most common demographic risk factor in breast cancer. The underlying cellular signaling mechanisms responsible for the age-associated rise in disease incidence have not yet been determined. Studies presented herein aim to elucidate age-related changes in the extracellular signal-regulated kinases, ERK1/2 and ERK5, of the mitogen-activated protein kinase (MAPK) pathway, and in the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway. Further, the role of the MEK5-ERK5 cascade in breast cancer cell proliferation, migration, and invasion was analyzed. In addition, several series of novel MEK5 inhibitors were characterized with regard to both efficacy and selectivity. In vitro assessment revealed distinct patterns of kinase expression and activation among the three breast cancer cell lines evaluated. In a spontaneous model of breast cancer, the expression and activation of ERK5 increased with age in tumor tissue, while no changes were observed in adjacent normal mammary tissue. Pharmacological inhibition of ERK5 decreased cell migration and invasion in a cellular model of triple-negative breast cancer. In addition, studies involving single and dual delivery of kinase inhibitors further promote targeting ERK5 in breast cancer due to its role in the upregulation of the related ERK1/2 and Akt pathways and suggest ERK5 exhibits specialized patterns of activation with regard to distinct tumor subtypes. The patterns of expression strongly indicate the need for individual tailoring of pharmaceutical interventions based on patient hormonal status and age and suggest the important role of the novel protein kinase, ERK5, in cell invasion and migration. The characterization of a series of diphenyl aniline compounds revealed a putative MEK5 inhibitor capable of reducing cell growth and reverting the epithelial-to-mesenchymal transition in triple-negative breast cancer cells. Full characterization of the MEK5-ERK5 cascade in breast cancer will assist in the development of more targeted inhibitors, thereby reducing toxicity and increasing efficacy in select patient cohorts.