Characterization of genetic events involved in docetaxel resistance in breast cancer
A model of docetaxel resistance in breast tumours was established in two breast cancer cell lines MCF-7 and MDA-MB-231. This was the first description of docetaxel resistant breast cancer cell lines. As an initial global analysis of the genetic events involved in docetaxel resistance, comparative genomic hybridisation (CGH) was used on the DNA extracted from the resistant cell compared to the parental cells. This allowed a unique insight into the specific chromosomal regions that were modified as resistance to docetaxel developed. The resistant cells exhibited a variety of chromosomal modifications from their parental cells. Most notable was the common region of gain of chromosome 7q and loss of chromosome 10q between the two resistant cell lines. Once modified chromosomal regions were identified, the subsequent aim of the study was to further characterise the regions and to identify candidate genes contained with in them. It was demonstrated that P-glycoprotein encoded on chromosome 7q21.1 was over expressed in the resistant cells and that this over expression contributed to the resistance. However it was discovered for the first time that, in addition to P-glycoprotein, the expression of additional genes (Hsp-27 and 14.3-3&'947;) contained on chromosome 7q, was altered. In addition, decreased expression of Bcl-2 was shown to be associated with docetaxel resistance. The identification of alteration of genomic regions and the modification of gene expression identified in this study make a significant original contribution to the understanding of the molecular events involved in docetaxel resistance.