PMID- 25789974
OWN - NLM
STAT- MEDLINE
DCOM- 20151130
LR  - 20211203
IS  - 2041-4889 (Electronic)
VI  - 6
IP  - 3
DP  - 2015 Mar 19
TI  - Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates 
      lapatinib resistance in breast cancer.
PG  - e1699
LID - 10.1038/cddis.2015.65 [doi]
AB  - 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.
FAU - Farrugia, M K
AU  - Farrugia MK
AD  - 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.
FAU - Sharma, S B
AU  - Sharma SB
AD  - 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.
FAU - Lin, C-C
AU  - Lin CC
AD  - 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.
FAU - McLaughlin, S L
AU  - McLaughlin SL
AD  - The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 
      26506, USA.
FAU - Vanderbilt, D B
AU  - Vanderbilt DB
AD  - 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.
FAU - Ammer, A G
AU  - Ammer AG
AD  - The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 
      26506, USA.
FAU - Salkeni, M A
AU  - Salkeni MA
AD  - 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.
FAU - Stoilov, P
AU  - Stoilov P
AD  - 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.
FAU - Agazie, Y M
AU  - Agazie YM
AD  - 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.
FAU - Creighton, C J
AU  - Creighton CJ
AD  - Department of Medicine and Dan L Duncan Cancer Center, Division of Biostatistics, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Ruppert, J M
AU  - Ruppert JM
AD  - 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.
LA  - eng
GR  - P20 RR016440/RR/NCRR NIH HHS/United States
GR  - S10RR026378/RR/NCRR NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
GR  - P30 RR032138/RR/NCRR NIH HHS/United States
GR  - P20 RR016477/RR/NCRR NIH HHS/United States
GR  - P20GM103434/GM/NIGMS NIH HHS/United States
GR  - P30GM103488/GM/NIGMS NIH HHS/United States
GR  - S10 RR026378/RR/NCRR NIH HHS/United States
GR  - S10 RR020866/RR/NCRR NIH HHS/United States
GR  - P20 GM103434/GM/NIGMS NIH HHS/United States
GR  - P30 GM103488/GM/NIGMS NIH HHS/United States
GR  - P30 RR032138/GM103488/GM/NIGMS NIH HHS/United States
GR  - R01 CA127405/CA/NCI NIH HHS/United States
GR  - RR020866/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150319
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (KLF4 protein, human)
RN  - 0 (KLF5 protein, human)
RN  - 0 (Klf4 protein, mouse)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (MCL1 protein, human)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Quinazolines)
RN  - 0VUA21238F (Lapatinib)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Breast Neoplasms/*drug therapy/genetics/pathology
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/*biosynthesis
MH  - Lapatinib
MH  - Mice
MH  - Myeloid Cell Leukemia Sequence 1 Protein/*biosynthesis/genetics
MH  - Quinazolines/administration & dosage
MH  - Receptor, ErbB-2/genetics
MH  - Signal Transduction/drug effects
PMC - PMC4385942
EDAT- 2015/03/20 06:00
MHDA- 2015/12/15 06:00
PMCR- 2015/03/01
CRDT- 2015/03/20 06:00
PHST- 2014/11/12 00:00 [received]
PHST- 2015/02/10 00:00 [revised]
PHST- 2015/02/12 00:00 [accepted]
PHST- 2015/03/20 06:00 [entrez]
PHST- 2015/03/20 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - cddis201565 [pii]
AID - 10.1038/cddis.2015.65 [doi]
PST - epublish
SO  - Cell Death Dis. 2015 Mar 19;6(3):e1699. doi: 10.1038/cddis.2015.65.