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

Eswaran Devarajan, Aysegul A. Sahin, Jack S. Chen, Raghu R. Krishnamurthy, Neeraj Aggarwal, Anne Marie Brun, Anna Sapino, Fan Zhang, Dhawal Sharma, Xiao He Yang, Ann D. Tora, Kapil Mehta

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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.

Original languageEnglish
Pages (from-to)8843-8851
Number of pages9
JournalOncogene
Volume21
Issue number57
DOIs
Publication statusPublished - Dec 12 2002

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Keywords

  • Apoptosis
  • Breast cancer
  • Caspases
  • Cyteine-proteases
  • Drug-resistance

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Devarajan, E., Sahin, A. A., Chen, J. S., Krishnamurthy, R. R., Aggarwal, N., Brun, A. M., Sapino, A., Zhang, F., Sharma, D., Yang, X. H., Tora, A. D., & Mehta, K. (2002). Down-regulation of caspase 3 in breast cancer: A possible mechanism for chemoresistance. Oncogene, 21(57), 8843-8851. https://doi.org/10.1038/sj.onc.1206044