To find out whether boosting cathepsin L levels enabled the cancer cells to restart homologous recombination, the researchers monitored sites of DNA damage tagged by RAD51, a protein that helps promote homologous recombination. The cells that had stopped growing did not display RAD51 foci, but these foci were prevalent in BOGA cells with reduced 53BP1. Removing cathepsin L from BOGA cells increased 53BP1 levels and diminished the number of RAD51 foci.
If cells can't perform homologous recombination, they turn to repair mechanisms such as NHEJ that can lead to jumbled chromosomes. However, after DNA-breaking doses of radiation, BOGA cells exhibited few chromosome defects. The number of these flaws climbed after the researchers stabilized 53BP1 levels by inhibiting cathepsin L or trimming its abundance.
The team then analyzed tumor samples from breast cancer patients. Researchers suspect that cathepsin L attacks 53BP1 by entering the nucleus. Samples from patients with BRCA1 mutations or with triple-negative breast canceran aggressive form of the diseaseshowed high levels of nuclear cathepsin L and reduced quantities of 53BP1. That suggests tumors in these patients hike the amounts of cathepsin L in the nucleus to break down 53BP1 and restore homologous recombination.
"It's a new pathway that explains how breast cancer cells lose 53BP1," says Gonzalo. How cancer cells boost nuclear cathepsin L levels is unclear, she notes.
Triple-negative breast cancers are currently identified by their lack of Her2 and the estrogen and progesterone receptors. The work suggests that another trio of measurementsthe amounts of 53BP1, cathepsin L, and vitamin D receptor in the nucleusmight help identify patients that are
|Contact: Rita Sullivan King|
Rockefeller University Press