By Nina Martin
“Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.”
–Excerpt from “My Medical Choice” by Angelina Jolie (New York Times, May 14, 2013)
Last week Angelina Jolie very publicly announced her preventative double mastectomy in response to testing positive for a mutation in the BRCA1 gene (Breast Cancer 1) gene. The New York Times and other news media sources gave excellent recounts of her story and of the basic facts known about this hereditary mutation—inheriting one mutant copy of BRCA1 from either parent can put a woman at an 80% risk for developing breast and/or ovarian cancer. Since her mother died of breast cancer in her 50’s, Jolie was at a higher risk for having the gene and thus underwent the expensive genetic testing. NYT and NPR have been stressing that this genetic mutation is rare and unless breast cancer is common in your family, the chances of having this mutation are small. You can access the debate on whether genetic testing for cancer genes should be included in health insurance here.
Since reading the NYT article last week, I went on a search for the underlying molecular causes and how a mutation in the BRCA1 gene can lead to cancer. This proved more difficult than I imagined because how the mutation leads to breast/ovarian cancer remains largely unknown (this is probably why NYT and NPR don’t even try to explain the causes).
For those of you with little science background, refer back to my “What is Cancer?” article for the basics on genes, proteins, and mutations that can lead to cancer. You cannot understand any cancer research without knowing what genes, proteins, and mutations are!
In the “What is Cancer?” article, we showed you that many factors can lead to the formation of tumors. We emphasized that sometimes cells are damaged by, for example, UV rays which leads to a release of signals that trigger programmed cell death or apoptosis. Another end result of damaging a cell is that the DNA is damaged—but not so badly that the cell must die, but signals must be released to trigger the repair of the DNA. When the signals are released, certain proteins attach to the DNA and replace the damaged parts with new ones. BRCA1 is a protein that is vital for this DNA repair mechanism as shown below.
The BRCA gene is found in all cells of the body (not just breast cells). The BRCA gene encodes for a protein that functions as a tumor suppressor. Tumor suppressors are a large family of proteins that identify when a cell is not working properly—like when it has been damaged by UV and either the cell undergoes DNA repair or apoptosis. A well-studied example of a tumor suppressor protein is p53 which, when activated, either stops the cell from growing (senescence), initiates DNA repair, or, if the cell is too damaged, triggers apoptosis. It has been long been known that mutations in tumor suppressors like p53 lead to the development of cancer because of impaired cell signaling that governs DNA repair and apoptosis.
Despite knowing it is a tumor suppressor and it acts to repair damaged DNA, it remains perplexing why mutations in a gene that is essential for DNA damage repair in all cells would be associated with the predisposition to only breast and ovarian cancers rather than an increased susceptibility to all types of cancer. It is very interesting to know that men can carry this mutation and pass on to their children, but it does not cause cancer in males.
I can easily understand why p53 mutations lead to cancer since they mess up cell death, leading to uncontrolled cell growth, but I found it doubly perplexing how a damaged DNA repair mechanism can lead to cancer. After doing a quick literature search on PubMed, I learned that it’s not just the BRCA mutation that causes cancer, but also a subsequent secondary mutation that damages key growth regulation proteins which cannot be repaired without BRCA1. The Columbia Medical Center (and researchers) put out a great article in 2007. Remember this is just an example of what could happen.
In the proposed scenario, the patient inherits the BRCA1 mutation, but then a secondary DNA damage event happens in a different tumor suppressor protein—in the above scenario it’s a tumor suppressor protein called PTEN. In normal cases, it’s ok if PTEN gets damaged—BRAC1 repairs it. In an abnormal situation, BRCA1 is mutated and can’t perform its repair function. So when PTEN is damaged, this leads to uncontrolled cell growth and possible tumor formation. This is why the risk of getting this kind of breast cancer is so low in the general population—if no one in your family has this mutated gene, the chances of having a spontaneous mutation is very low. However, if you do have this inherited mutation, the chances of getting a second mutation in a tumor suppressor like PTEN is 80% for women.
Because the knowledge about BRCA1 is still patchy, this could create a perfect opportunity for the spread of misinformation. NYT and NPR handled this rather well—sticking to general facts and avoiding any scientific discussion. However, this also makes things more confusing. I hope this article shed some light on how BRCA mutations may lead to cancer.