An investigation of the molecular mechanisms of docetaxel resistance in breast cancer cells

• Main Author: Sangrithi-Wallace, Jay N.
• Published: University of Aberdeen 2009
• Subjects: 616.994; Breast : Docetaxel
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509214

Comparative genomic hybridization has previously identified regions of genomic alteration associated with docetaxel resistance in MCF-7 and MDA-MB-231 breast cancer cell lines. Amplification of chromosome 7q and loss of chromosome 10q were two common regions of alteration in these docetaxel-resistant breast cancer cells. Loss of chromosome 12p was associated with resistance in MCF-7 cells only. In the present study, the minimal region of chromosome 12p loss was identified by BAC-fine-mapping in. Bio-informatics was used to identify candidate genes within the minimal region of alternative on chromosomes 7q, 10q and 12p. This study identified that docetaxel resistance was associated with decreased mRNA and protein expression of both transforming acidic coiled-coil protein 2 (TACC2) on chromosome 10q, and dual specificity phosphatase 16 (DUSP16) on chromosome 12p, in the MCF-7 docetaxel-resistant cell line. However, in the MDA-MB-231 docetaxel-resistant cell line, expression of TACC2 was increased at the mRNA level and decreased at the protein level whilst expression of DUSP16 was not investigated. Silencing the expression of these genes, using siRNA technology, in the docetaxel sensitive MCF-7 cell line did not make them more resistant to docetaxel. Therefore, while decreased expression of TACC2 and DUSP16 are associated with docetaxel resistance it is unlikely that these changes are causative of drug resistance in this cell line model. Furthermore, this study demonstrated that increased mRNA and protein expression of caveolin 1 (CAV1) was associated with resistance to docetaxel in the MDA-MB-231 docetaxel-resistant cell line. Decreasing CAV1 expression, by siRNA, in this cell line increased sensitivity to docetaxel. Increased expression of CAV1, therefore, may contribute, at least partially, to the mechanism of acquired resistance to docetaxel in MDA-MB-231 breast cancer cells. It is therefore imperative to confirm these results in breast cancer tissues.