Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer

Cell Death & Disease
M K FarrugiaJ Michael Ruppert

Abstract

The Kruppel-like transcription factors (KLFs) 4 and 5 (KLF4/5) are coexpressed in mouse embryonic stem cells, where they function redundantly to maintain pluripotency. In mammary carcinoma, KLF4/5 can each impact the malignant phenotype, but potential linkages to drug resistance remain unclear. In primary human breast cancers, we observed a positive correlation between KLF4/5 transcript abundance, particularly in the human epidermal growth factor receptor 2 (HER2)-enriched subtype. Furthermore, KLF4/5 protein was rapidly upregulated in human breast cancer cells following treatment with the HER2/epidermal growth factor receptor inhibitor, lapatinib. In addition, we observed a positive correlation between these factors in the primary tumors of genetically engineered mouse models (GEMMs). In particular, the levels of both factors were enriched in the basal-like tumors of the C3(1) TAg (SV40 large T antigen transgenic mice under control of the C3(1)/prostatein promoter) GEMM. Using tumor cells derived from this model as well as human breast cancer cells, suppression of KLF4 and/or KLF5 sensitized HER2-overexpressing cells to lapatinib. Indicating cooperativity, greater effects were observed when both genes were depleted. KLF4/5-def...Continue Reading

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Citations

Feb 18, 2016·Stem Cells International·Giuseppina CatanzaroElisabetta Ferretti
Aug 19, 2015·Drug Development Research·Sriganesh B Sharma, John Michael Ruppert
Apr 2, 2016·ILAR Journal·Amanda L Hudson, Emily K Colvin
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Dec 20, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Jianping ZhangXian Wang
Aug 13, 2018·ACS Biomaterials Science & Engineering·Mingqi WangHua Wei

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Methods Mentioned

BETA
immunoprecipitation
xenograft
transgenic
RNAseq
ChIP
ChIP-seq
PCR
Assay
FCS

Software Mentioned

genefu
Bioconductor
Image J
R
GraphPad Prism
GraphPad
FCS Express
BD CellQuest Pro
R package

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