Elsevier

Neoplasia

Volume 16, Issue 3, March 2014, Pages 247-256.e2
Neoplasia

KIF14 Promotes AKT Phosphorylation and Contributes to Chemoresistance in Triple-Negative Breast Cancer1,2

https://doi.org/10.1016/j.neo.2014.03.008Get rights and content
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open access

Abstract

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.

Abbreviations

TNBC
triple-negative breast cancerestrogen-receptor negative/progesterone-receptor negative/Her2 negative
siRNA
small-interfering RNA
LC50
median lethal concentration

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1

This work was supported by the Simmons Cancer Center Support grant (5P30 CA 142543–03), T32CA136515 from the National Cancer Institute, and Susan G. Komen Foundation Postdoctoral Fellowship (to S.M.S.), an Alcon Research Institute Young Investigator Award (to T.W.C.), and The Southland Financial Corporation Distinguished Chair in Geriatric Research (to J.W.S). L.L. was supported by Welch (I-1665) and National Institute of Health (R01CA168761). This work was performed in laboratories constructed with support from National Institutes of Health grant C06 RR30414. This work was also supported in part by the Indiana Clinical and Translational Sciences Institute funded, in part, by the National Institutes of Health, National Center for Advancing Translational Sciences, and Clinical and Translational Sciences Awards (TR000163; to T.W.C.). Conflict of interest: The authors declare no conflict of interest.

2

This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com.