KLF4 defines the efficacy of the epidermal growth factor receptor inhibitor, erlotinib, in triple-negative breast cancer cells by repressing the EGFR gene.
Background: Triple-negative breast cancer (TNBC) is characterized by high rates of recurrence and poor overall survival. This is due, in part, to a deficiency of targeted therapies, making it essential to identify therapeutically targetable driver pathways of this disease. While epidermal growth fac...
| Publicado en: | Breast Cancer Research Vol. 22; no. 1; pp. 1 - 15 |
|---|---|
| Autores principales: | , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
6/18/2020
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=143854436&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 143854436 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 6/18/2020 vid: 22 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 143854436 143854436 NLM32552913 143854436 10.1186/s13058-020-01305-7 NLM32552913 143854436 ppf: 1 ppct: 14 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: KLF4 defines the efficacy of the epidermal growth factor receptor inhibitor, erlotinib, in triple-negative breast cancer cells by repressing the EGFR gene. aug: au: Roberts, Melyssa S. Anstine, Lindsey J. Finke, Viviane S. Bryson, Benjamin L. Webb, Bryan M. Weber-Bonk, Kristen L. Seachrist, Darcie D. Majmudar, Parth R. Keri, Ruth A. affil: Department of Pharmacology, School of Medicine, Case Western Reserve University, 44106, Cleveland, OH, USA sug: subj: Breast Neoplasms Antineoplastic Agents Pharmacodynamics Breast Neoplasms Drug Therapy Proteins Metabolism Breast Neoplasms Metabolism Phosphorylation Cell Physiology Drug Effects Receptors, Cell Surface Antagonists and Inhibitors Human Receptors, Cell Surface Proteins Breast Neoplasms Pathology Female Receptors, Cell Surface Metabolism Signal Transduction Cell Movement Drug Effects Apoptosis Drug Effects Validation Studies Comparative Studies Evaluation Research Multicenter Studies Clinical Assessment Tools Coping Health Inventory for Parents Impact of Events Scale Female ab: Background: Triple-negative breast cancer (TNBC) is characterized by high rates of recurrence and poor overall survival. This is due, in part, to a deficiency of targeted therapies, making it essential to identify therapeutically targetable driver pathways of this disease. While epidermal growth factor receptor (EGFR) is expressed in 60% of TNBCs and drives disease progression, attempts to inhibit EGFR in unselected TNBC patients have had a marginal impact on outcomes. Hence, we sought to identify the mechanisms that dictate EGFR expression and inhibitor response to provide a path for improving the utility of these drugs. In this regard, the majority of TNBCs express low levels of the transcription factor, Krüppel-like factor 4 (KLF4), while a small subset is associated with high expression. KLF4 and EGFR have also been reported to have opposing actions in TNBC. Thus, we tested whether KLF4 controls the expression of EGFR and cellular response to its pharmacological inhibition.Methods: KLF4 was transiently overexpressed in MDA-MB-231 and MDA-MB-468 cells or silenced in MCF10A cells. Migration and invasion were assessed using modified Boyden chamber assays, and proliferation was measured by EdU incorporation. Candidate downstream targets of KLF4, including EGFR, were identified using reverse phase protein arrays of MDA-MB-231 cells following enforced KLF4 expression. The ability of KLF4 to suppress EGFR gene and protein expression and downstream signaling was assessed by RT-PCR and western blot, respectively. ChIP-PCR confirmed KLF4 binding to the EGFR promoter. Response to erlotinib in the context of KLF4 overexpression or silencing was assessed using cell number and dose-response curves.Results: We report that KLF4 is a major determinant of EGFR expression and activity in TNBC cells. KLF4 represses transcription of the EGFR gene, leading to reduced levels of total EGFR, its activated/phosphorylated form (pEGFR), and its downstream signaling intermediates. Moreover, KLF4 suppression of EGFR is a necessary intermediary step for KLF4 to inhibit aggressive TNBC phenotypes. Most importantly, KLF4 dictates the sensitivity of TNBC cells to erlotinib, an FDA-approved inhibitor of EGFR.Conclusions: KLF4 is a major regulator of the efficacy of EGFR inhibitors in TNBC cells that may underlie the variable effectiveness of such drugs in patients. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|