Journal article
Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles
Science translational medicine, Vol.6(229), pp.229ra43-229ra43
03/26/2014
DOI: 10.1126/scitranslmed.3007965
PMCID: PMC4176609
PMID: 24670687
Abstract
The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.
Details
- Title: Subtitle
- Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles
- Creators
- Lauren M. Zasadil - Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USAKristen A. Andersen - Univ Wisconsin, Mol & Cellular Pharmacol Training Program, Madison, WI 53705 USADabin Yeum - Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USAGabrielle B. Rocque - Univ Wisconsin, Dept Med, Madison, WI 53705 USALee G. Wilke - Univ Wisconsin, Dept Surg, Madison, WI 53705 USAAmye J. Tevaarwerk - Univ Wisconsin, Dept Med, Madison, WI 53705 USARonald T. Raines - Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53705 USAMark E. Burkard - Univ Wisconsin, Dept Med, Madison, WI 53705 USABeth A. Weaver - Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.6(229), pp.229ra43-229ra43
- Publisher
- Amer Assoc Advancement Science
- DOI
- 10.1126/scitranslmed.3007965
- PMID
- 24670687
- PMCID
- PMC4176609
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Number of pages
- 10
- Grant note
- R01CA140458; P30 CA014520 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32CA009135 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) 9U54TR000021; T32 GM008688; T32 CA009135 / National Center for Advancing Translational Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) T32GM008688 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 03/26/2014
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984700653302771
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