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Experimental and Molecular Therapeutics

Targeting proteasomes in antiestrogen resistant breast cancer cells

Hong Liu, Binghui Li and Ruth Lupu
Hong Liu
Northwestern Healthcare Research Institute and Northwestern University Feinberg School of Medicine, Chicago, IL
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Binghui Li
Northwestern Healthcare Research Institute and Northwestern University Feinberg School of Medicine, Chicago, IL
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Ruth Lupu
Northwestern Healthcare Research Institute and Northwestern University Feinberg School of Medicine, Chicago, IL
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DOI:  Published May 2007
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AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

Abstract

1450

The majority of breast tumors are hormone receptors positive and estrogens stimulate their growth. The principle for treating this type of breast cancer is based on blocking the cancer cells from the hormone-induced growth, the goal of antiestrogen therapy. However, there is a sub-population of hormone receptor-positive breast tumors that do not respond to antiestrogen therapy. Almost all of the breast tumors that initially respond to the therapy become resistant. Designing effective treatment for antiestrogen resistance is a big challenge. The proteasome is a complex of proteins with several types of enzyme activities responsible for degradating of many important intracellular proteins. Inhibition proteasome activities would cause the protein accumulation, leading to cell malfunction, eventually cell growth inhibition and cell death. Proteasome inhibitors show anti-tumor activity in many malignancies, including breast cancer. However, the proteasome has not been tested as a therapeutic target in antiestrogen resistant breast cancer. To investigate if proteasome inhibitors exhibit effective anti-tumor activities in antiestrogen resistant breast cancer, we tested the effects of two proteasome inhibitors on proteasome activity and cytotoxicity in antiestrogen sensitive MCF-7, acquired antiestrogen resistant MCF-7/F and de novo antiestrogen resistant MDA-MB-231 cells. Two proteasome inhibitors used in this study are GSI (z-Leu-Leu-Nle-CHO) and MG132 (z-Leu-Leu-Leu-CHO). Cytotoxicity was measured using a MTT assay. The effect on cell growth was assessed by changes in expression of p21waf-1/cip1 and cyclin D1. Early apoptosis was evaluated by PARP cleavage. Proteasome activity was assessed by measuring ubiquitinated protein accumulation. Our results show that the proteasome inhibitors exhibited strong anti-tumor activity in MCF-7, MCF-7/F and MDA-MB-231 cells. The inhibitors inhibited proteasome activities, which correlates with induced p21 and decreased cyclin D1 protein levels in a concentration dependent manner in all three cell lines. However, the proteasome inhibitors might inhibit cell growth via different mechanisms in these cells. The inhibitors down-regulated ER, inhibited MAPK phosphorylation and increased AKT phosphorylation in MCF-7 cells. They induced apoptosis and increase AKT phosphorylation, but had no significant effect on MAPK phosphorylation in MCF-7/F cells. The inhibitors induced obvious apoptosis and inhibited MAPK phosphorylation, but had no detectable effect on AKT in MDA-MB-231 cells. In summary, antiestrogen resistance is a big pitfall of antiestrogen therapy for breast cancer. Here, our results suggest a possible therapeutic strategy by targeting proteasomes as a potential therapy for antiestrogen resistant breast cancer and proteasome inhibitors in combination with AKT/MAPK blockers might be superior to the single agent treatment in breast cancer.

Footnotes

  • 98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

  • American Association for Cancer Research
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Cancer Research: 67 (9 Supplement)
May 2007
Volume 67, Issue 9 Supplement
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Targeting proteasomes in antiestrogen resistant breast cancer cells
Hong Liu, Binghui Li and Ruth Lupu
Cancer Res May 1 2007 (67) (9 Supplement) 1450;

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Targeting proteasomes in antiestrogen resistant breast cancer cells
Hong Liu, Binghui Li and Ruth Lupu
Cancer Res May 1 2007 (67) (9 Supplement) 1450;
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Cancer Research Online ISSN: 1538-7445
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Journal of Cancer Research ISSN: 0099-7013
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