PULLMAN, Wash. — Not only are there many kinds of cancer, but even cancers that we think of as distinct can act differently in different people. Breast cancer is a case in point. But following initial discouragement upon realizing how differently breast cancer can behave in different women, scientists finally discovered that the distinguishing factor in such cases is the normally protective p53 gene.
If there were a molecular category for guardian angels, it would likely be the tumor suppressor genes, including p53. Cancer is the uncontrolled growth and proliferation of cells. Normally, the delicate balance of a cell’s life is controlled by the interplay between the tumor suppressors, which restrain cell growth, and proto-oncogenes, which stimulate it. When a cell is exposed to mutating factors — radiation or carcinogenic chemicals, for example — p53 multiplies and stops the cell from going through the complete cycle necessary for cell division, whereupon the cell’s repair machinery kicks in to fix the damage.
Sometimes, however, p53 mutates also. When that happens, it fails to produce the proteins that repress the cell’s growth.
Patients with mutant p53 become resistant to treatment. In fact, the proliferating cells can develop other mutations and become more and more resistant.
Sayed Daoud’s approach is to focus on the p53 gene itself by using a combination of drugs, one to attack the tumor itself and one to inhibit the effect of the mutated p53. When the effect of the mutated p53 is inhibited, the cell usually will, as Daoud puts it, “crash and die.”
The procedure works in vitro. Test-tube cells become very responsive to the treatment.
Now Daoud, associate professor of pharmaceutical sciences, wants to know exactly how the process works. He recently received a grant for nearly $200,000 from the Susan G. Komen Breast Cancer Foundation to explore the mechanism involved.
This much is known: in order to divide, a cell must go full cycle through distinct phases: G1 (gap 1), S (or “synthetic,” during which the cell duplicates its DNA), and then G2. The cell can then enter mitosis and divide into two, whereupon the new cells can grow and repeat the cycle.
When a cell is damaged, p53 normally will increase its ranks and arrest cell development at the G1 stage. Once damage is repaired, the cell will continue through the cycle.
However, if the gene is mutated, the cell will not stop at the G1 stage and so repair will not occur. The mutant p53 will arrest cell development in the G2 phase. But that’s too late for repair. The cell continues toward mitosis, and the defects are transmitted to the new cells.
So what is needed is to inhibit the suppression of the mutant p53 in the G2 phase. This way the cell goes into mitosis very quickly, and it dies before it can divide again. “This is the novelty of our work,” says Daoud, who has high hopes for his project’s clinical effectiveness in treating breast cancer. His laboratory will conduct pre-clinical testing this summer.
The Susan G. Komen Breast Cancer Foundation is the largest private funder of research dedicated solely to breast cancer. The foundation focuses on potentially high-impact research projects that may not be fundable by other agencies.
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