Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

Iain Brown, Kawan Shalli, Sarah McDonald, Susan Emma Moir, A. W. Hutcheon, Steven Darryll Heys, Andrew Craig Schofield

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Introduction 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.

Original languageEnglish
Pages (from-to)R601-R607
Number of pages7
JournalBreast Cancer Research
Volume6
Issue number5
DOIs
Publication statusPublished - Aug 2004

Keywords

  • breast cancer
  • docetaxel
  • drug resistance
  • gene expression
  • p27
  • DEPENDENT KINASE INHIBITOR
  • DOWN-REGULATION
  • CYCLE ARREST
  • MICE LACKING
  • LUNG-CANCER
  • P27(KIP1)
  • APOPTOSIS
  • TUBULIN
  • ACTIVATION
  • CARCINOMA

Cite this

Brown, I., Shalli, K., McDonald, S., Moir, S. E., Hutcheon, A. W., Heys, S. D., & Schofield, A. C. (2004). Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells. Breast Cancer Research, 6(5), R601-R607. https://doi.org/10.1186/bcr918

Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells. / Brown, Iain; Shalli, Kawan; McDonald, Sarah; Moir, Susan Emma; Hutcheon, A. W.; Heys, Steven Darryll; Schofield, Andrew Craig.

In: Breast Cancer Research, Vol. 6, No. 5, 08.2004, p. R601-R607.

Research output: Contribution to journalArticle

Brown, I, Shalli, K, McDonald, S, Moir, SE, Hutcheon, AW, Heys, SD & Schofield, AC 2004, 'Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells', Breast Cancer Research, vol. 6, no. 5, pp. R601-R607. https://doi.org/10.1186/bcr918
Brown I, Shalli K, McDonald S, Moir SE, Hutcheon AW, Heys SD et al. Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells. Breast Cancer Research. 2004 Aug;6(5):R601-R607. https://doi.org/10.1186/bcr918
Brown, Iain ; Shalli, Kawan ; McDonald, Sarah ; Moir, Susan Emma ; Hutcheon, A. W. ; Heys, Steven Darryll ; Schofield, Andrew Craig. / Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells. In: Breast Cancer Research. 2004 ; Vol. 6, No. 5. pp. R601-R607.
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AU - Heys, Steven Darryll

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N2 - Introduction 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.

AB - Introduction 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.

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