The DNA repair–breast cancer connection
The gene known as BRCA1 (for “breast cancer susceptibility gene 1”) has a storied history. It was the first gene identified as contributing to familial breast cancer risk, and its discovery in 1990 led scientists and doctors to accept the theory that breast cancer could be inherited. Now experts know that having a mutation that inactivates the breast cancer gene increases a woman’s chances of getting breast cancer about sixfold.
While scientists know much about how dysfunctional BRCA1 protein leads to cancer, they know little about what the protein actually does in cells. In a paper published in Nature this fall, Patrick Sung, D.Phil., professor of molecular biophysics and biochemistry and of therapeutic radiology, reports findings that shed light on the function of the breast cancer protein in the repair of broken DNA.
Sung has been studying the homologous recombination method of DNA repair for more than 20 years. This DNA repair mechanism takes place when the cell is about to divide, after it has duplicated its chromosomes—bundles of double-stranded DNA—but before each chromosome and its duplicate have split off into separate cells. In homologous recombination, a large number of proteins function together to repair a DNA break in one chromosome by copying the broken section from the duplicate chromosome to patch up the break. First, for a short distance on either side of the break, one strand of the DNA is shaved away to form a single-stranded end. Next, each single-stranded end inserts itself between the two strands of the duplicate chromosome in order to copy the damaged DNA section. Like an interloper at a dance, the single-stranded end gets between the other chromosome’s two strands, pushing one of them aside and forming a structure called a displacement loop or D-loop.
In 1994, working in yeast, Sung discovered that a protein called RAD51 attaches itself to the single-stranded end of the broken DNA and leads the invasion of the duplicate chromosome. In 1997, another lab learned that this invader protein physically interacts with the breast cancer protein. “We have to study this,” Sung thought to himself when he heard the news. All of a sudden, his research became related to breast cancer.
But yeast, the model system Sung had been using, does not have the breast cancer protein. In order to study the interactions between the invader protein and the breast cancer protein, Sung had to shift his research focus from yeast to humans—or, rather, human cells and proteins.
Sung and his team developed a method to isolate a significant quantity of the BRCA1 protein as a complex with a partner protein called BARD1. The researchers performed experiments to test D-loop formation by RAD51 with and without the breast cancer protein and its partner. Those tests revealed that the duo helps the invader protein to form D-loops, and results from experiments done in human cells confirmed these findings.
This new information suggests, Sung said, that in breast cancer patients with mutations in the breast cancer gene, defective DNA repair likely leads to cancer development. In this regard, knowledge of how the breast cancer protein works could aid in drug development.
The findings could also empower patients to make important choices about their treatment. In patients with a family history of breast cancer, for example, doctors could sequence the breast cancer gene and the gene encoding its partner to look for mutations that might impede the pair’s functioning. Further, it would be possible, Sung said, to recreate a patient’s protein duo in the laboratory and test its DNA repair abilities to better assess the patient’s cancer risk. “Being able to apply this type of system to look at patient mutations will ultimately help patients to make decisions, like whether to get a mastectomy as a preventive measure,” Sung said. “It’s a really big deal. It’s very important. Because it’s a huge decision for anyone to make.”