KLF4 defines the efficacy of the epidermal growth factor receptor inhibitor, erlotinib, in triple-negative breast cancer cells by repressing the EGFR gene

摘要: Triple-negative breast cancer (TNBC) is characterized by high rates of recurrence and poor overall survival. This due, in part, to a deficiency targeted therapies, making it essential identify therapeutically targetable driver pathways this disease. While epidermal growth factor receptor (EGFR) expressed 60% TNBCs drives disease progression, attempts inhibit EGFR unselected TNBC patients have had marginal impact on outcomes. Hence, we sought the mechanisms that dictate expression inhibitor response provide path for improving utility these drugs. In regard, majority express low levels transcription factor, Kruppel-like 4 (KLF4), while small subset associated with expression. KLF4 also been reported opposing actions TNBC. Thus, tested whether controls cellular its pharmacological inhibition. was transiently overexpressed MDA-MB-231 MDA-MB-468 cells or silenced MCF10A cells. Migration invasion were assessed using modified Boyden chamber assays, proliferation measured EdU incorporation. Candidate downstream targets KLF4, including EGFR, identified reverse phase protein arrays following enforced The ability suppress gene signaling RT-PCR western blot, respectively. ChIP-PCR confirmed binding promoter. Response erlotinib context overexpression silencing cell number dose-response curves. We report major determinant activity represses gene, leading reduced total activated/phosphorylated form (pEGFR), intermediates. Moreover, suppression necessary intermediary step aggressive phenotypes. Most importantly, dictates sensitivity erlotinib, an FDA-approved EGFR. regulator efficacy inhibitors may underlie variable effectiveness such drugs patients.