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Specific kinesin expression profiles associated with taxane resistance in basal-like breast cancer

  • Preclinical study
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Abstract

Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. Kinesins are intracellular transport proteins that interact with microtubules, which are also the mechanistic target for taxanes. We investigated the relationship between taxane resistance in BLBC and kinesins using both expression and functional studies. Kinesin (KIF) expression was evaluated in three settings in relation to taxane resistance: (i) the NCI-60 cancer cell lines, (ii) pre-treatment samples from four BLBC patient cohorts receiving neoadjuvant chemotherapy regimens with and without taxanes, and (iii) post-treatment samples from residual breast cancer following neoadjuvant taxane-containing chemotherapy. We used a novel functional approach to gene modification, validation-based insertional mutagenesis, to select kinesin-overexpressing clones of BLBC cells for evaluation of related mechanisms of taxane resistance. In the NCI-60 cell line dataset, overexpression of the kinesin KIFC3 is significantly correlated with resistance to both docetaxel (P < 0.001) and paclitaxel (P < 0.001), but not to platinum-based chemotherapy, including carboplatin (P = 0.49) and cisplatin (P = 0.10). Overexpression of KIFC3 and KIF5A in pre-chemotherapy samples similarly predicted resistance to paclitaxel in the MDACC cohorts (P = 0.01); no KIF predicted resistance to fluorouracil–epirubicin–cyclophosphamide or cisplatin in BLBC patient cohorts treated without taxanes. KIF12 is the most overexpressed KIF gene in post-chemotherapy taxane-resistant residual breast cancers (2.8-fold-change). Functional studies established that overexpression of KIFC3, KIF5A, and KIF12 were specific in mediating resistance to docetaxel and not vincristine or doxorubicin. Mutation of the ATP-binding domain of a kinesin abolished its ability to mediate docetaxel resistance. Overall, kinesin overexpression correlates with specific taxane resistance in BLBC cell lines and tissues. Our results suggest a novel approach for drug development to overcome taxane resistance in breast cancer through concurrent or sequential use of kinesin inhibitors.

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Abbreviations

ATP:

Adenosine triphosphate

BLBC:

Basal-like breast cancer

CC:

Cleveland Clinic

DFCI:

Dana-Farber Cancer Institute

EORTC:

European Organization for Research and Treatment of Cancer

GI50:

Concentration required to reduce growth by 50%

KIF:

Kinesin superfamily

MDACC:

MD Anderson Cancer Center

pCR:

Pathological complete response

PLR:

Penalized Logistic Regression

RD:

Residual disease (invasive cancer)

RT-PCR:

Reverse transcriptase-polymerase chain reaction

TGI:

Concentration required for total growth inhibition

VBIM:

Validation-based insertional mutagenesis

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Acknowledgments

We thank the participating patients for their contributions. We also thank Charissa Peterson for her able technical assistance. The National Institutes of Health and the William Randolph Hearst Foundations funded this study. MHT is a Lee Foundation (Singapore) Fellow and the Ambrose Monell Foundation Cancer Genomic Medicine Clinical Fellow, and GB is an NCI R25T Fellow. GTS is the co-holder of the Zapis Chair of Breast Cancer Research; GRS is the Distinguished Scientist of the Cleveland Clinic; and CE is the holder of the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and is an American Cancer Society Clinical Research Professor. No funding organization was involved in the design, conduct, analysis, writing or submission of this manuscript.

Competing interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue (NE-50), Cleveland, OH, 44195, USA

    Min Han Tan, Gurkan Bebek, Mohammed S. Orloff & Charis Eng

  2. Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Sarmishtha De & George R. Stark

  3. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Gurkan Bebek, G. Thomas Budd, George R. Stark & Charis Eng

  4. Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Gurkan Bebek

  5. Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Mohammed S. Orloff, Robert Wesolowski, G. Thomas Budd & Charis Eng

  6. Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Erinn Downs-Kelly

  7. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Charis Eng

  8. Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH, 44195, US

    Charis Eng

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  1. Min Han Tan
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  2. Sarmishtha De
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  9. Charis Eng
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Corresponding author

Correspondence to Charis Eng.

Additional information

Min Han Tan and Sarmishtha De contributed equally and should be considered joint first authors.

G. Thomas Budd, George R. Stark and Charis Eng are joint senior authors.

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Tan, M.H., De, S., Bebek, G. et al. Specific kinesin expression profiles associated with taxane resistance in basal-like breast cancer. Breast Cancer Res Treat 131, 849–858 (2012). https://doi.org/10.1007/s10549-011-1500-8

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  • DOI: https://doi.org/10.1007/s10549-011-1500-8

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