ArticleCell death & disease2015
Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer.
Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- Multi-Protein Profiling Reveals High Nuclear KFL-4 Expression as a Predictor of Poor Overall Survival in Breast Cancer: A Retrospective Cohort Study.International journal of molecular sciences · 2026Article
- KLF4 in cancer chemoresistance: molecular mechanisms and therapeutic implications.Discover oncology · 2025Review
- Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding.Cancer letters · 2025Review
- Adipocytes-induced ANGPTL4/KLF4 axis drives glycolysis and metastasis in triple-negative breast cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- Role of YY1 in the Regulation of Anti-Apoptotic Gene Products in Drug-Resistant Cancer Cells.Cancers · 2023Review
- New insights into KLFs and SOXs in cancer pathogenesis, stemness, and therapy.Seminars in cancer biology · 2023Review
- Roles and Regulation of BCL-xL in Hematological Malignancies.International journal of molecular sciences · 2022Review
- Functional impact of multi-omic interactions in breast cancer subtypes.Frontiers in genetics · 2022Article
- Novel Antibody Exerts Antitumor Effect through Downregulation of CD147 and Activation of Multiple Stress Signals.Journal of oncology · 2022Article
- Long Non-Coding RNAs in Diffuse Large B-Cell Lymphoma.Non-coding RNA · 2020Article
- KLF4 defines the efficacy of the epidermal growth factor receptor inhibitor, erlotinib, in triple-negative breast cancer cells by repressing the EGFR gene.Breast cancer research : BCR · 2020Article
- Whole exome sequencing of multiple meningiomas with varying histopathological presentation in one patient revealed distinctive somatic mutation burden and independent clonal origins.Cancer management and research · 2019Article
- NADPH oxidase 4 regulates anoikis resistance of gastric cancer cells through the generation of reactive oxygen species and the induction of EGFR.Cell death & disease · 2018Article
- Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is.Genes & development · 2018Article
- CRISPR-ON-Mediated KLF4 overexpression inhibits the proliferation, migration and invasion of urothelial bladder cancerOncotarget · 2017Article
- KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth.Oncogene · 2017Article
- Article
- FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis.Journal of lipid research · 2017Article
- Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions.Oncotarget · 2017Article
- Characterization and phylogenetic analysis of Krüppel-like transcription factor (KLF) gene family in tree shrews (Tupaia belangeri chinensis).Oncotarget · 2017Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
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-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL). Moreover, MCL1 was upregulated by lapatinib in a KLF4/5-dependent manner, and enforced expression of MCL1 in KLF4/5-deficient cells restored drug resistance. In addition, combined suppression of KLF4/5 in cultured tumor cells additively inhibited anchorage-independent growth, resistance to anoikis and tumor formation in immunocompromised mice. Consistent with their cooperative role in drug resistance and other malignant properties, KLF4/5 levels selectively stratified human HER2-enriched breast cancer by distant metastasis-free survival. These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.
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