Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells.
BACKGROUND
Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects.


METHODS
We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively.


RESULTS
Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively).


CONCLUSIONS
This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies.
Brown
Iain
I
Department of Surgery, University of Aberdeen, Medical School, Aberdeen, UK. i.brown@abdn.ac.uk
Shalli
Kawan
K
McDonald
Sarah L
SL
Moir
Susan E
SE
Hutcheon
Andrew W
AW
Heys
Steven D
SD
Schofield
Andrew C
AC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D043823:Taxoids / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077143:Docetaxel