Human Gene Set: HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_4NM_DN
Standard name
HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_4NM_DN
Systematic name
M1185
Brief description
Genes down-regulated in MCF7 cells (breast cancer, normal TP53 [GeneID=7157]) undergoing aberrant mitosis and necrosis after treatment wiht 4 nM docetaxel [PubChem=148124].
Full description or 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.
Collection
C2: Curated CGP: Chemical and Genetic Perturbations
Source publication
Pubmed 17099726 Authors: Hernández-Vargas H,Palacios J,Moreno-Bueno G
