title: Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer.
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.
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA.
authors: M K
authors: MK
authors: Farrugia
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA.
authors: S B
authors: SB
authors: Sharma
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors: C-C
authors: CC
authors: Lin
authors: The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors: S L
authors: SL
authors: McLaughlin
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA.
authors: D B
authors: DB
authors: Vanderbilt
authors: The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors: A G
authors: AG
authors: Ammer
authors: 1] The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA [2] Department of Medicine, West Virginia University, Morgantown, WV 26506, USA.
authors: M A
authors: MA
authors: Salkeni
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA [3] The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors: P
authors: P
authors: Stoilov
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA [3] The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors: Y M
authors: YM
authors: Agazie
authors: Department of Medicine and Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: C J
authors: CJ
authors: Creighton
authors: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA [3] The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
authors: J M
authors: JM
authors: Ruppert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D000077341:Lapatinib; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D000077341:Lapatinib; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715467:KLF4 protein, human; C492214:KLF5 protein, human; C000715468:Klf4 protein, mouse; C579095:MCL1 protein, human; C508053:ERBB2 protein, human