Analysis of a New Human Caspase in Breast Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Sug Hyung Lee, M.D., Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6FB-0082 Award: $51,527
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2000)
The growth of cancer is caused by an imbalance between the rates at which cancer cells are produced through cell division and the rate at which they die through a natural cell death process known as apoptosis. Defects in the key regulatory proteins the apoptosis pathways allow cancer cells to survive, accumulate genetic errors, and eventually result in metastatic spread. Thus, if defects in the apoptosis pathways could be either corrected or the blockage points rerouted within the cell, then apototsis could resume and tumor size become reduced.

The final stage of apoptosis is caused a type of molecule within cells, which are called caspases. The caspases represent a group of structurally similar proteins that cleave other proteins- so-called "proteases." In short, caspases cause the cell to digest itself. To date

mammalian caspases comprise a group of at least fourteen members. Each caspase may play a unique role in linking certain types of cell death stimuli (e.g., radiation, chemotherapy, or immune-based) to a specific apoptotic response protein pathway.

The specific focus of this CBCRP-funded project is ‘caspase 12.’ This caspase has been identified in mice, but not yet in humans. Recently, we found evidence that a new gene, which is very similar to mouse caspase 12, resides on human chromosome 11 at a location frequently deleted in human tumors - including breast cancers. It is well known that such deletions in chromosomes represent a common mechanism for inactivating genes. We plan to isolate this gene and determining its role in breast cancer. Our specific aims include cloning the human counterpart to caspase 12, studying its protein structure, and identifying the proteins that bind to it and control its activity. Our ultimate goal will be to find ways to directly ‘activate’ this and other caspases, even when other elements in the apoptosis pathways of breast cancer cells are missing or defective. And, these results will explain how a key process in normal breast epithelial cells becomes defective as cancer progresses.

The clinical significance derived from these studies may provide a new breast cancer genetic marker for assessing either risk of recurrence or predicting response to chemo- and radiation therapy.


Final Report (2002)
The growth of cancer is caused by an imbalance between the rates at which cancer cells are produced through cell division and the rate at which they die through a natural cell death process known as programmed cell death (also referred to as apoptosis). Defects in apoptosis pathways allow cancer cells to survive for prolonged periods of times, accumulate genetic errors, and live in a suspended state that permits metastatic spread. By permitting damaged tumor cells to survive, blocks to apoptosis in cancer cells are also responsible in large part for resistance to chemotherapy and radiation therapy.

Apoptosis is triggered by turning-on a type of molecule within cells, called caspases. The caspases represent a group of structurally similar proteins that cleave other proteins, so-called "proteases." These cell death proteases are the ultimate executioners responsible for apoptosis, thus studying caspase activation mechanisms and their dysfunction in cancer cells is important for understanding how cancers develop and how they become resistant to therapy.

The purpose of this study was to find new caspase genes on human chromosome 11q22. By searching the public database, we identified sequences that show homology to mouse caspase-12. Also, we found a novel caspase recruit domain (CARD)-containing gene on chromosome 11q22 and cloned the full-length cDNA of this gene. This protein is relatively short, comprised essentially of only a CARD which shares high identity to caspase-1 CARD. We named it as COP (CARD Only Protein). This protein binds to pro-caspase-1 and RIP2. We showed that COP inhibits caspase-1-induced IL-1 beta processing. Further studies on COP function with apoptosis, expression in breast cancer and possible mutations in breast cancer will be accomplished in the future.

Cop, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Lee SH, Stehlik C, Reed JC
Yr: 2001 Vol: 276 Nbr: 37 Abs: Pg:34495-500