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Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance

Oncogene volume 21, pages 8843–8851 (2002)Cite this article

Abstract

Caspase-3 is a member of the cysteine protease family, which plays a crucial role in apoptotic pathways by cleaving a variety of key cellular proteins. Caspase-3 can be activated by diverse death-inducing signals, including the chemotherapeutic agents. The purpose of this study was to determine the levels of caspase-3 expression in breast tumor samples and to determine whether alterations in its expression can affect their ability to undergo apoptosis. Primary breast tumor and normal breast parenchyma samples were obtained from patients undergoing breast surgery and the expression of caspases-3 was studied. Similarly, normal mammary epithelial cells and several established mammary cancer cell lines were studied for caspases-3 expression by reverse transcriptase-polymerase chain reaction, Northern blot analysis, and Western blot analysis. Approximately 75% of the tumor as well as morphologically normal peritumoral tissue samples lacked the caspase-3 transcript and caspase-3 protein expression. In addition, the caspases-3 mRNA levels in commercially available total RNA samples from breast, ovarian, and cervical tumors were either undetectable (breast and cervical) or substantially decreased (ovarian). Despite the complete loss of caspase-3, the expression levels of other caspases, such as caspase-8 and caspase-9, were normal in all of the tumor samples studied. The sensitivity of caspase-3-deficient breast cancer (MCF-7) cells to undergo apoptosis in response to doxorubicin and other apoptotic stimuli could be augmented by reconstituting caspase-3 expression. These results suggest that the loss of caspases-3 expression may represent an important cell survival mechanism in breast cancer patients.

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Acknowledgements

This work was supported by a grant from the US Department of Defense (DAMD17-01-1-0645) to K Mehta and by American Health Assistance Foundation to N Aggarwal. We thank Drs J Dai and K Keyomarsi for providing cell lines and Ms Mariann Crapanzano for the editorial help.

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Authors and Affiliations

  1. Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Eswaran Devarajan, Jack S Chen, Fan Zhang, Dhawal Sharma & Kapil Mehta

  2. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Aysegul A Sahin

  3. Department of Pathology, University of North Texas Health Science Center, Fort Worth, 76107, Texas, TX, USA

    Raghu R Krishnamurthy, Neeraj Aggarwal & Anne-Marie Brun

  4. Department of Biomedical Sciences and Human Oncology, Torino, Italy

    Anna Sapino

  5. Department of Pathology, Northwestern University Medical School, Evanston, 60201, Illinois, IL, USA

    Xiao-He Yang & Ann D Tora

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  1. Eswaran Devarajan
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  2. Aysegul A Sahin
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Correspondence to Kapil Mehta.

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Devarajan, E., Sahin, A., Chen, J. et al. Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene 21, 8843–8851 (2002). https://doi.org/10.1038/sj.onc.1206044

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