Enzyme helps cancer cells avoid genetic instability
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| Susana Gonzalo |
Cancer cells are resourceful survivors with plenty of tricks for
staying alive. Researchers have uncovered one of these stratagems, showing how
cells lacking the tumor suppressor BRCA1 can resume one form of DNA repair,
sparing themselves from stagnation or death. The study appears in the January
21st issue of The Journal of Cell Biology. The
BRCA1 protein helps to mend double-strand DNA breaks by promoting homologous
recombination. Without it, cells can amass broken, jumbled, and fused chromosomes,
which may cause them to stop growing or die. Although cells lacking BRCA1 seem
like they should be vulnerable, loss of the protein instead seems to boost
abnormal growth.
Recent studies have shown that cells lacking BRCA1 compensate by
cutting back on 53BP1. This protein helps orchestrate a different DNA repair
mechanism, nonhomologous end joining (NHEJ), and it thwarts a key step in
homologous recombination. Researchers think that, in cells without BRCA1, 53BP1
spurs excessive NHEJ that can cause fatal chromosomal chaos. But with 53BP1 out
of the way, the cells are able to resume homologous recombination. That might
explain why cells that lack BRCA1 and eliminate 53BP1 can withstand traditional
chemotherapy compounds and PARP inhibitors, a new generation of anti-cancer
drugs that are in clinical trials. But how do cancer cells turn down 53BP1?
Researchers previously found that certain mutant fibroblasts
increase production of cathepsin L, a protease that destroys 53BP1.
BRCA1-deficient cancer cells take advantage of the same mechanism, according to
a team of researchers led by Susana Gonzalo from the Washington University
School of Medicine. When they cultured breast cancer cells that were missing
BRCA1, the cells stopped growing. After two weeks of lethargy, however, some
cells, which the researchers dubbed BOGA cells (BRCA1-deficient cells that
overcome growth arrest), began to divide again. These cells showed increased
levels of cathepsin L and reduced amounts of 53BP1. Eliminating cathepsin L
from BOGA cells or dosing them with vitamin D, a cathepsin L inhibitor,
prevented the decline in 53BP1 abundance.
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 cancer -- an aggressive form of the disease -- showed 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 measurements -- the amounts of 53BP1, cathepsin L, and
vitamin D receptor in the nucleus -- might help identify patients that are
resistant to current breast cancer treatments. These people might respond to
cathepsin inhibitors, some of which are undergoing animal testing. These
compounds might steer the cells away from homologous recombination and leave
them vulnerable to other therapies.
Source: Rockefeller University Press
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