Health: Shedding light on breast cancer's family roots
Molecular model of the BRCT domain of the BRCA1 protein, a disease hot spot for hereditary early onset breast cancer. J.N.M. Glover, University of Alberta
It is estimated that over 23,000 new cases of breast cancer will be diagnosed in Canada in 2011. A minority, but growing, number of cases will be classified as early onset breast cancer - an aggressive form of the disease that strikes women in their late twenties or early thirties. Not only is the disease hard to treat, it often runs in families.
University of Alberta researcher Mark Glover and his research group have led the way in understanding the genetic underpinnings of hereditary early onset breast cancer, including being the first researchers to determine the molecular structure of a key region of the BRCA1 gene, mutations in which put patients at increased risk for the disease. Now, with the aid of a database of genetic mutations obtained through breast cancer screening and the Canadian Light Source, Dr. Glover's team has begun to unravel how changes in BRCA1 lead to breast cancer. The research could lead to better genetic tests to diagnose the condition and even treat the disease and other forms of cancer.
“BRCA1 was identified with early onset hereditary breast cancer. We had almost no idea what it did in the cell but we did know that it put people at high risk,” explains Glover. “Understanding the three dimensional structure [of regions of the gene called domains] gives us a clue about how the protein functions and understand how mutations change that function.”
It turns out that BRCA1 plays a crucial role in how a cell responds to damage to its DNA, alerting the cell to problems by flagging sites of DNA damage (like how a word processor’s spell check flags misspelled words). BRCA1 then summons other proteins to repair the damage and, perhaps most importantly, stops the cell from replicating until repairs are made. Mutations in BRCA1 affect how effectively a cell can repair DNA damage, allowing typos in the genetic code to perpetuate and possibly give rise to cancerous cells.
“It’s kind of like the cell’s traffic cop,” he says.
Dr. Glover and his collaborators have focused their work on a domain of BRCA1 called BRCT. Researchers consider BRCT a ‘disease hot spot’ as half of the 120 known mutations in the domain are suspected to lead to breast cancer. The mutations are a change in a single amino acid ‘letter’ in the 2000 amino acids in the protein’s genetic code. Glover and his team looked at mutants that affected how BRCA1 interacted with other proteins in one of two ways, narrowing the field of mutants down to six variants.
“We identified candidates where the mutation left the protein’s structure largely okay, but seemed to affect the protein’s function,” says Glover. “We know from the very earliest studies that some of these very subtle changes are responsible for very aggressive forms of the disease.”
The mutant proteins were grown as crystals and their three dimensional structure was determined using synchrotrons. Five of the variants were analyzed at the CLS while the sixth was taken to the Advanced Light Source in Berkley, California.
The teams’ results support the somewhat counter-intuitive observation that mutants which result in little or no change in the structure of the protein can have a big impact on how it works. In this case, two of the variants appeared to significantly affect how well BRCA1 binds to other proteins involved in the DNA repair process while mutants that resulted in bigger changes to the protein’s structure seemed to have little effect on BRCA1’s effectiveness.
“We had guessed that a lot of these mutations would really disrupt how BRCA1 interacted, but they didn’t,” muses Glover. “We thought we could make predictions without doing the hard work, and that’s not always the case. We have to think carefully about what these mutations are doing.”
While none of the mutants that were analyzed are known to lead to early onset breast cancer, Dr. Glover believes that the insights gained from this study coupled with clinical data from genetic screening programs and patient histories will make it possible for researchers to better identify mutants in BRCA1 and other proteins involved in DNA repair. As DNA damage is the culprit behind all cancers, better understanding of how our cells’ repair system works will benefit earlier detection and treatment of all forms of the disease.
Dr. Glover’s immediate goal is to narrow down the BRCT mutations he and other researchers have found in order to provide more accurate tests for those at risk for hereditary early onset breast cancer.
“It’s important that we do what we can since these early onset cancers are so aggressive and difficult to treat. It can be catastrophic for families,” he notes. “People in these families [afflicted with hereditary breast cancer] want to get tested, want to know if they are at risk. Many are actually relieved to know, but it is a hard thing to go through testing and then get an ambiguous result. We hope to clarify that.”
-Matthew Dalzell
Reference: N. Coquelle, R. Green and J.N.M. Glover. Impact of BRCA1 BRCT Domain Missense Substitutions on Phosphopeptide Recognition. Biochemistry, 2011, 50. DOI: 10.1021/bi2003795
Last modified: 2012-01-19 17:01:02