The Role of PAK2 in Breast Cancer Cell Death

Institution: Scripps Research Institute
Investigator(s): Gary Bokoch, Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3PB-0062 Award: $529,149
Award Type: Request for Applications
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (1997)
The breast cells of pregnant women undergo dramatic changes in structure during the process of milk production, which must then be reversed as the child is weaned. This normal reshaping process requires the now unwanted milk-producing cells to undergo a process known as programmed cell death. The breast cells respond to hormonal signals by undergoing biochemical changes that cause the cells to effectively kill themselves. Normally developing breast tissue is controlled by a balance between growing cells and dying cells. When this process becomes abnormal, so that the cells no longer die as they should, then the remaining cells can grow out of control and become breast cancers.

The mortality associated with breast cancer is highly correlated with its ability to spread from the original site in the breast to other areas of the body. An important observation has been made that the breast cancer cells most resistant to the process of cell death are also those that are most likely to effectively move into other tissues. Thus, there is a relationship between an abnormal resistance to cell death and increased spread of breast cancers. Up until now, the basis for this relationship has been unknown.

We have discovered a protein present in breast cancers that can regulate both cell death and cell movement. Because of its regulatory activities in both of these areas, this protein, called PAK2, is a likely candidate to explain the connection that has been noted between resistance to cell death and the ability of breast cancers to invade the body. PAK2 normally becomes active during cell death responses we have studied in other systems. We will determine whether PAK2 is also an important mediator of breast cancer cell death responses. It is possible that PAK2 does not get activated normally to induce cell death in the cells that develop into breast cancers, and we will examine this possibility in our studies. We will investigate whether PAK2 can then regulate the ability of the death-resistant breast cancer cells to move from other body sites. Our studies will provide new insights into the problem of how breast cancers might be more effectively induced to die by chemotherapeutic drugs, and will also suggest mechanisms that might allow us to inhibit the spread of breast cancers.

Final Report (2001)
We have been investigating the processes that regulate the critical balance between the growth of breast cancer cells and their death. When the balance shifts away from normal levels of cell death, then the cells proliferate abnormally and cancers develop. In particular, our studies have focused on a protein, termed p21activated kinase or PAK, as an important regulator of this balance. PAK is a member of a family of enzymes known as kineses, which add chemical phosphate groups onto other proteins. This phosphorylation reaction changes the activity and function of the modified targets. This action of PAK is likely to play important roles Oh regulating breast call growth and death under both normal and pathologic circumstances. We are trying to ~: understand how this regulation can become pathological.

We made significant progress over the period of this award. We initially investigated the regulation by PAK of another kinase, termed Jun kinase that induces cell death. We showed that PAK was required but not sufficient for Jun kinase activation in certain cell types. Surprisingly, we found that PAK activity could be antic cell death in certain other cells. We identified a novel mechanism for this effect, establishing that PAK could phosphorylate and inactivate the pro death protein known as Bad. A second mechanism is being investigated PAK activity was found to be abnormally high in certain breast cancer cell lines. We initiated studies to determine why PAK was activated and what the consequences were for cell death and motility. (PAK was shown by our studies to also regulate the ability of cells to migrate and for cancer cells to metastasize). This work is still ongoing, but we have found that PAK activity is increased due to mix localization within the cell. We have identified a mechanism for this, and have found activation to be dependent on binding of the cell to the surrounding tissue matrix. We plan to continue the latter studies to determine how PAK is mix localized and what the consequences are for the ability of breast cancer cells to grow, move and survive. This work will allow us to know a lot about the suitability of PAKs as potential therapeutic targets for treating certain breast cancers.

Cutting edge: p21-activated kinase (PAK) is required for fas-induced JNK activation in Jurkat Cells
Periodical:Journal of Immunology
Index Medicus: J Immunol
Authors: Rudel T, Zenke FT, Chuang T-H, and Bokoch GM
Yr: 1998 Vol: 160 Nbr: Abs: Pg:7-11