This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-09-1224v1 69/20/8035    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by De, S. Articles by Stark, G. R. PubMed PubMed Citation Articles by De, S. Articles by Stark, G. R.

Overexpression of Kinesins Mediates Docetaxel Resistance in Breast Cancer Cells

Departments of ¹ Genetics and ² Pathology, Case Western Reserve University, Case Comprehensive Cancer Center, and ³ Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio

Requests for reprints: George R. Stark, Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-444-3900; Fax: 216-444-3279; E-mail: starkg{at}ccf.org.

Key Words: Insertional mutagenesis • microtubule depolymerization

Resistance to chemotherapy remains a major barrier to the successful treatment of cancer. To understand mechanisms underlying docetaxel resistance in breast cancer, we used an insertional mutagenesis strategy to identify proteins whose overexpression confers resistance. A strong promoter was inserted approximately randomly into the genomes of tumor-derived breast cancer cells, using a novel lentiviral vector. We isolated a docetaxel-resistant clone in which the level of the kinesin KIFC3 was elevated. When KIFC3 or the additional kinesins KIFC1, KIF1A, or KIF5A were overexpressed in the breast cancer cell lines MDA-MB231 and MDA-MB 468, the cells became more resistant to docetaxel. The binding of kinesins to microtubules opposes the stabilizing effect of docetaxel that prevents cytokinesis and leads to apoptosis. Our finding that kinesins can mediate docetaxel resistance might lead to novel therapeutic approaches in which kinesin inhibitors are paired with taxanes. [Cancer Res 2009;69(20):8035–42]