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.
Grotsky, D.A., et al. 2013. J. Cell Biol. doi:10.1083/jcb.201204053.
Rockefeller University Press: http://www.rupress.org/
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
People who suffer from mental health issues also suffer from its stigma. Portraying mental illness as a good thing helps no one
The inventor of a breakthrough DNA test for Down syndrome says the technology can be used to screen people for cancer.The Hong Kong scientist who invented a simple blood test to show pregnant women if their babies have Down syndrome is now testing a similar technology for cancer.
Dr Jeremy Farrar of Wellcome Trust says international community is belatedly taking actions necessary to stem tide of disease
Miniature stomachs gastric organoids will help in study of ulcers and could be used in future to repair patients stomachs
The story of the vaccines development is just one part of a rich and intertwined history of scientific discovery and controversy
A highly sensitive blood test for Ebola exists, so why isn't it being used to test all returning health workers from West Africa? Because the virus isn't in the blood in the first stages of infection.
Drinking beverages enriched with compounds found in cocoa beans improved older adults' performances on a memory test – but there's a catch
A 700-year-old caribou dropping from northern Canada holds surprisingly well-preserved viruses. There's no evidence the viruses are dangerous, but they are scientifically interesting.
The New England Journal of Medicine published an editorial against quarantining people who have worked with Ebola patients in Africa. Renee Montagne speaks with Dr. Lindsey Baden, one of the authors.
Surgeons in Australia say they have performed the first heart transplant using a "dead heart".