KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer.
Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative, "triple-negative" breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.
Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cell Biology University of Texas Southwestern Medical Center, Dallas, TX, USA.
Stina M
SM
Singel
Department of Cell Biology University of Texas Southwestern Medical Center, Dallas, TX, USA.
Crystal
C
Cornelius
Cell Biology, Harvard Medical School, Boston, MA, USA.
Elma
E
Zaganjor
Department of Cell Biology University of Texas Southwestern Medical Center, Dallas, TX, USA.
Kimberly
K
Batten
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Venetia R
VR
Sarode
Department of Chemistry, Yale University, New Haven, CT, USA.
Dennis L
DL
Buckley
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Yan
Y
Peng
Clinical Laboratory Services, University of Texas Southwestern Medical Center, Dallas, TX, USA.
George B
GB
John
Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Hsiao C
HC
Li
Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Navid
N
Sadeghi
Department of Cell Biology University of Texas Southwestern Medical Center, Dallas, TX, USA.
Woodring E
WE
Wright
Department of Cell Biology University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lawrence
L
Lum
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
Timothy W
TW
Corson
Department of Cell Biology University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Jerry.Shay@utsouthwestern.edu.
Jerry W
JW
Shay
D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006579:Heterozygote; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D020360:Neoadjuvant Therapy; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D015513:Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C502598:KIF14 protein, human; D016547:Kinesins