title: Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles.
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.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Zasadil
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Andersen
authors.forename: Dabin
authors.initials: D
authors.lastname: Yeum
authors.forename: Gabrielle B
authors.initials: GB
authors.lastname: Rocque
authors.forename: Lee G
authors.initials: LG
authors.lastname: Wilke
authors.forename: Amye J
authors.initials: AJ
authors.lastname: Tevaarwerk
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
authors.forename: Mark E
authors.initials: ME
authors.lastname: Burkard
authors.forename: Beth A
authors.initials: BA
authors.lastname: Weaver
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007399:Interphase / Q000187:drug effects; D008875:Middle Aged; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000627:therapeutic use* / Q000633:toxicity; D008941:Spindle Apparatus / Q000187:drug effects / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D017239:Paclitaxel