KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer

Stina M. Singel, Crystal Cornelius, Elma Zaganjor, Kimberly Batten, Venetia R. Sarode, Dennis L. Buckley, Yan Peng, George B. John, Hsiao C. Li, Navid Sadeghi, Woodring E. Wright, Lawrence Lum, Timothy W. Corson, Jerry W. Shay

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere2
Pages (from-to)247-256
Number of pages10
JournalNeoplasia (United States)
Volume16
Issue number3
DOIs
StatePublished - 2014

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Triple Negative Breast Neoplasms
Kinesin
Phosphorylation
docetaxel
Breast
gemcitabine
Biomarkers
Mutation
Carboplatin
Progesterone Receptors

ASJC Scopus subject areas

  • Cancer Research

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KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer. / Singel, Stina M.; Cornelius, Crystal; Zaganjor, Elma; Batten, Kimberly; Sarode, Venetia R.; Buckley, Dennis L.; Peng, Yan; John, George B.; Li, Hsiao C.; Sadeghi, Navid; Wright, Woodring E.; Lum, Lawrence; Corson, Timothy W.; Shay, Jerry W.

In: Neoplasia (United States), Vol. 16, No. 3, e2, 2014, p. 247-256.

Research output: Contribution to journalArticle

Singel, Stina M. ; Cornelius, Crystal ; Zaganjor, Elma ; Batten, Kimberly ; Sarode, Venetia R. ; Buckley, Dennis L. ; Peng, Yan ; John, George B. ; Li, Hsiao C. ; Sadeghi, Navid ; Wright, Woodring E. ; Lum, Lawrence ; Corson, Timothy W. ; Shay, Jerry W. / KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer. In: Neoplasia (United States). 2014 ; Vol. 16, No. 3. pp. 247-256.
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AU - Singel, Stina M.

AU - Cornelius, Crystal

AU - Zaganjor, Elma

AU - Batten, Kimberly

AU - Sarode, Venetia R.

AU - Buckley, Dennis L.

AU - Peng, Yan

AU - John, George B.

AU - Li, Hsiao C.

AU - Sadeghi, Navid

AU - Wright, Woodring E.

AU - Lum, Lawrence

AU - Corson, Timothy W.

AU - Shay, Jerry W.

PY - 2014

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AB - 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.

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