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Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

Oncogene volume 26, pages 2902–2913 (2007)Cite this article

Abstract

Among microtubule-targeting agents, docetaxel has received recent interest owing to its good therapeutic index. Clinical trials have underlined its potential for the treatment of advanced breast cancer, although little is known about its molecular mode of action in this context. We characterized the molecular changes induced by docetaxel in two well-known human breast carcinoma cell lines. Two mechanisms of action according to drug concentration were suggested by a biphasic sensitivity curve, and were further validated by cell morphology, cell cycle and cell death changes. Two to four nanomolar docetaxel induced aberrant mitosis followed by late necrosis, and 100 nM docetaxel induced mitotic arrest followed by apoptosis. Passing through mitosis phase was a requirement for hypodiploidy to occur, as shown by functional studies in synchronized cells and by combining docetaxel with the proteasome inhibitor MG132. Transcriptional profiling showed differences according to cell line and docetaxel concentration, with cell cycle, cell death and structural genes commonly regulated in both cell lines. Although p53 targets were mainly induced with low concentration of drug in MCF7 cells, its relevance in the dual mechanism of docetaxel cytotoxicity was ruled out by using an isogenic shp53 cell line. Many of the genes shown in this study may contribute to the dual mechanism by which docetaxel inhibits the growth of breast cancer cells at different concentrations. These findings provide a basis for rationally enhancing docetaxel therapy, considering lower concentrations, and better drug combinations.

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Acknowledgements

We thank Dr Cayetano von Kobbe for the generation of shp53 MCF7 cells. We are grateful to CNIO Confocal Microscopy and Cytometry Units. This work was supported by Ministerio de Educación y Ciencia, Grant Reference PTR1995-0753-OP and Ministerio de Ciencia y Tecnología SAF2001-0065 and SAF2004-08258-C02-01. GMB is junior investigator of the Ramón y Cajal Program 2004.

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Author notes

  1. J Palacios

    Present address: Servicio de Anatomía Patológica, HHUU Virgen del Rocío, Avda. Manuel Siurot S/N, 41013, Sevilla

  2. G Moreno-Bueno

    Present address: Instituto de Investigaciones Biomedicas (IIB)-Alberto Sols, Unidad de Biología Molecular y Celular del Cáncer, C/Arturo Duperier 4, 28029, Madrid, Spain

Authors and Affiliations

  1. Breast and Gynaecological Cancer Group, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain

    H Hernández-Vargas, J Palacios & G Moreno-Bueno

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Correspondence to G Moreno-Bueno.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Hernández-Vargas, H., Palacios, J. & Moreno-Bueno, G. Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis. Oncogene 26, 2902–2913 (2007). https://doi.org/10.1038/sj.onc.1210102

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