Fighting Breast Cancer Using p53
In 2005, approximately 200,000 people in the United States were diagnosed with breast cancer and 40,000 people died from breast cancer (American Cancer Society, Inc. 2006a); compared to the 14,000 people a year that die from HIV/AIDS (Central Intelligence Agency 2006), this is a prevalent problem. Breast cancer is the second most deadly type of cancer in the
The obstruction of p53 in cells is the most common defect present in all types of cancers. Cells that lack even only a portion of this p53 protein are especially resistant to standard therapies that are used to help minimize the side effects of cancer (Center for Biotechnology Information 2005). Among the many proteins in a cell, p53 is statistically the most commonly mutated protein of all in any type of cancer (McGill 1999). The p53 protein was discovered in 1979 by Arnold Levine,
DNA is essential in all cellular forms of life and controls the cell’s function, appearance, and biological development (Wikimedia Foundation, Inc. 2006b). When a cell replicates, it passes on identical copies of its DNA to new cells. A cell becomes cancerous when its DNA is mutated, which means it has been damaged or improperly replicated. If the DNA is mutated, all of the new cells’ DNA will be mutated as well and they will all be cancerous cells (Itahana 1998). While normal cells in the body will grow, divide, and then die; cancer cells do not die. Healthy cells realize the limitations of a physical body and will program themselves to die when there is not enough space for them or there are no more nutrients available in their area. Because cancer cells have a mutation that provides the cells with a selective growth advantage, they aggressively disregard all instructions to die (Itahana 1998). This selective growth advantage allows cancer cells to survive longer than normal cells because their programmed cell death is not active when p53 is obstructed. This causes the cells to divide uncontrollably and form a large group of cancer cells, called a tumor (American Cancer Society, Inc. 2006b). Cancer cells also have the ability to spread to other parts of the body where more resources are available, creating more tumors. When the tumor suppressor gene does not repair damaged DNA in cancer cells, the result could be long illness, death, or hereditary cancer (Wikimedia Foundation, Inc. 2006a).
All cells go through the cell cycle, which is their life cycle of growth, replication, division, and eventually death. The tumor suppressor protein, p53, plays a vital role in the cell cycle. After the cell’s growth phase, it has to pass a p53 checkpoint in order to proceed into the replication phase. At this checkpoint, p53 checks every single portion of the cell’s DNA for mutations. If small mutations are detected, p53 instructs the cell to repair the damage and then move on into the replication phase. If a large mutation is detected, p53 instructs to cell to die so that it cannot pass on this mutation (Anon 2006). When this checkpoint was discovered, p53 earned the title “the guardian of the genome” due to the fact that it protects the cell’s damaged DNA from replicating and being passed on to new cells (Anon 2001). If a questionable mutation is detected, p53 can slow down the cell cycle or stop it. Since p53 is obstructed in cancer cells, their cell cycle goes much faster due to absence of this checkpoint (Anon 2006).
Properly regulating p53 can keep cells healthy and prevent cancer (Wikimedia Foundation, Inc. 2006c). There is a delicate balance in p53 activity; unwarranted activation can be catastrophic to developing cells, but inactivity can lead to cancers. This tumor suppressor protein is regulated both negatively and positively. The stability of p53 is a complex process which involves many proteins and molecules that respond to overactive p53 in a negative feedback loop; this is when excess p53 activates certain proteins and molecules to reduce its affect. Positive feedback loops are activated by scarcity of p53 to increase its affect (Landes Bioscience 2005). In healthy cells, p53 is continually produced and degraded to maintain this balance; degradation plays a key role in overactive p53 (Lain 2003). These processes are sensitive to many forms of stress, such as, temperature, pH, and pressure. Homeostasis and the immune system help keep the body in a normal, healthy condition so that all of the processes can follow through smoothly.
Since p53 is obstructed in many cancer cases, restoring its innate tumor-suppressing mechanism will help fight against breast cancer. Since all healthy cells go through the p53 checkpoint during their development, inserting intact p53 into cancerous cells can activate this p53 checkpoint and cure cancer cells (Soussi 2006). Obstructed p53 proteins will not be a problem because new, healthy p53 can just be inserted into the cancer cells.
Although p53 is a powerful tumor suppressor protein, it does not work alone to fight cancer by simple insertion (Itahana 1998). Kinases and phosphorylating enzymes are proteins that “activate” or “energize” a molecule by adding a phosphate group to it from another high energy molecule (Ashcroft and Vousden 1999). Mdm2 is a protein that is stimulated by excess p53 and functions to minimize the amount of p53 in a cell. This is a key step in reducing overactive p53 in a healthy cell; however this is not a desirable effect in cancer cells (Gross 2006). Mdm2 binds to p53 and reduces its ability to activate gene expression and stop cell division, thereby interfering with p53’s control over DNA replication machinery. To restore p53’s function in cancer cells, kinases or phosphorylating enzymes need to be inserted into the cells to energize p53 and alter its structure. This allows p53 to carryout its function because Mdm2 cannot bind to p53’s new structure to deactivate it. By inserting kinases and phosphorylating enzymes into cancer cells, the p53 protein can activate the tumor suppressor gene to destroy cancer cells (Ashcroft and Vousden 1999).
Another tumor-suppressor protein, p14ARF, is known to be missing in about half of all breast cancer cases. However, missing p14ARF is not the sole component that can cause breast cancer in most cases. When p14ARF and p53 are both missing in a cell, a common result is cancer. This fact lead researchers to believe that p14ARF and p53 are somehow linked (Gjerset 2000). Additional research shows that p14ARF binds directly to Mdm2 on a different location than p53. Mdm2 can still interact with p53, but because p14ARF is also bound to Mdm2, it is deactivated. In this p14ARF-Mdm2-p53 protein complex, both Mdm2 and p53 are stabilized. This inhibits Mdm2’s activity and restores p53’s function. Therefore, the addition of p14ARF into breast cancer cells can lead to activation of p53 and stop cancer (Ashcroft and Vousden 1999).
Delivery of p53, kinases, phosphoylating enzymes, or p14ARF to cancerous cells can be a prevailing strategy in fighting breast cancer. However, these proteins cannot simply be injected into one’s blood stream or swallowed in a pill; they must be carefully inserted into the victim’s body and incorporated into their cells’ DNA. The proteins need to pass through the cell’s membrane, through the cell’s body, pass through the nuclear membrane, and be incorporated into the DNA. This can be done by gene therapy, which is when altered or foreign proteins are introduced into cells to fabricate a desired effect (Wikimedia Foundation, Inc. 2005). Experiments of introducing p53 into p53-deficient cells in a test tube have proven successful. The same experiments in rats depicted either the death of cancer cells or prevention of further division and survival of the rats. Although this has not been tested on humans yet, this hypothesis should still be taken into consideration (U.S. Department of Energy Office of Science, Human Genome Program 2005).
Injections of these proteins into a human body can be done through viral vector treatment. This procedure is a type of gene therapy that utilizes viruses to deliver genetic material into a cell, permanently changing that cell’s DNA. Since a virus infects its host by incorporating its DNA into the host’s DNA, scientists can modify viral DNA such that a desired protein is introduced to the host instead of a virus’s harmful effect. The specific virus used in this procedure is called a retrovirus. A retrovirus is a special type of viruses that can translate its own DNA into DNA that belongs in a living organism’s cell. The retrovirus’s ability to match these two different types of DNA together is what makes it so efficient in infecting its host cell (Wikimedia Foundation, Inc. 2006b). Viruses can therefore be used as a means of transportation to carry “good genes” into a cell. The virus functions to integrate a desired protein into the host’s DNA. As the cell replicates, the new cells created will also have the desired protein. Since the protein is now incorporated into the cells’ DNA, it can carryout its function (Gardlik et al 2005). If p53 is integrated into the DNA, it will follow through with its function and ignore the obstructed p53. If kinases or phosphorylating enzymes are integrated, they will alter p53’s structure to allow it to activate the tumor suppressor gene. If p14ARF is integrated, it will bind to Mdm2 to deactivate it and allow p53 to carryout its function. The p53 tumor suppressor protein is now ready to fight breast cancer.
Fighting breast cancer using p53 is a very promising treatment for the future. This treatment uses p53, kinases, phosphorylating enzymes, or p14ARF, which are all proteins that exist naturally in the body. The concern of many people that choose not to use chemotherapy, the introduction of drugs into the victim’s bloodstream, is that unnatural chemicals are introduced to their bodies (MayoClinic 2006). Using gene therapy is another positive aspect of this p53 treatment. Gene therapy is a method that has already been proven successful in reducing tumor size and can differentiate cancer cells from healthy cells. This is why p53 treatment surpasses radiation therapy; X-rays focused on the victim’s tumor attack all cells, not only the tumor cells, and lead to unnecessary death of healthy cells. Using gene therapy spares the healthy cells and kills the cancerous cells (BBC News 2000). This solution is also ideal because it has been tested in great detail at the
Although fighting breast cancer using p53 has much potential for the future, this treatment is limited by some constraints. First and foremost, this method is not in use yet. It needs to go through much more animal and human testing before it can be available on the market. Additionally, issues concerning the use of viruses as the choice of gene-carrier include weakening of the immune system and intoxication of DNA. If inserting a virus into one’s body weakens their immune system, there exist possibilities for sicknesses of other kinds to occur in the patient (U.S. Department of Energy Office of Science, Human Genome Program 2005). Scientists need to discover how much the immune system weakens, if this is a great amount, the treatment will not be worth the risk to the patient’s life. Given the nature of retroviruses, the inserted p53 gene is spontaneous and out of external control. The viral DNA may be integrated into many different parts of the host’s DNA and its effects may vary (U.S. Department of Energy Office of Science, Human Genome Program 2005). Since the p53 tumor suppressor protein is sensitive to many stresses, unwarranted activation may occur by external factors. This is bad because adding extra p53 to a cancer patient that has a low immune system, due to the virus used, can lead to over-active p53 because of the patient’s inability to maintain normal conditions in the body (Phillips 2006). Fighting breast cancer using p53 also has the common side effects of any other cancer treatment available today. Some of the most common side effects include bone marrow depletion, excessive bleeding, and hair loss (Phillips 2006). General constraints to this solution include the fact that every case of breast cancer is diverse and these differences need to be overcome in order to develop a universal treatment for breast cancer. Like all the different solutions available, this p53 solution has moral problems attached to it. Many researchers are arguing that the apoptotic death of cells isn’t necessary in fighting cancer. This type of cell death is immediate and programmed cell death that is induced by a protein, in this case the protein is p53. Radiobiologists have a particularly difficult problem with this type of cell death because slower, non-apoptotic death plays an important role in the cycle of a viable cell (McGill 1999). Finally, there is a major downfall in using p53 itself for any type of treatment. Although much more is known today about this tumor suppressor protein than was known in the 1970s, its function is still incompletely known. Researchers are working hard everyday to find out all they can about this powerful protein, but there are still limitations to what they can discover (McGill 1999).
Since the p53 solution is not currently in use due to certain hurdles that science needs yet to cross, breast cancer patients still have options to alleviate their symptoms and prolong their life spans. Today, tumors can be alleviated with a combination of surgery, chemotherapy, hormone therapy and radiation therapy. Through surgery, the doctor will either remove the entire breast or just the affected part of the breast; this depends on how severe the tumor is. Chemotherapy relies on drugs that interfere with cell division to kill cells (Wikimedia Foundation, Inc. 2006a). Hormone therapy removes or inactivates hormones so that cells lack proper hormones to grow, however it only works in breast cancer cases that are caused by hormonal factors (National Cancer Institute 2005). Radiation therapy uses an X-ray beam to kill the cells in that target area. The X-ray damages the cell’s DNA to make it impossible for the cell to divide (Wikimedia Foundation, Inc. 2006a). Tumors are infatuated with certain proteins that are produced by oncogenes, but can be poisoned by tumor suppressor proteins. Essentially, the drug of choice would function to stop this infatuation or provide poison to the tumor cells. There are some drugs that exist today which follow this function, for example Gleevec and Herceptin (Brody 2003). However, due to the recurrence of cancer, these drugs aren’t sufficient. Even when surgery, chemotherapy, hormone therapy and radiation therapy are all combined to fight cancerous cells, tumors have a tendency to recur. The ideal counterattack against cancer is to suppress it before it begins because once cancer has begun to grow, the fight against it is an enormously rough battle.
-Amy Shah
