Defeito do Gene do Cancer de peito do “reparo” dos cientistas
por
Brendon Nafziger, DOTmed News Associate Editor | April 06, 2010
So by knocking out the 53BP1 protein, the scientists appeared to be able to restore the HR pathway, and prevent chromosomal aberrations from building up. In the mice that had the 53BP1 protein turned off, the researchers found a 10-fold decrease in chromosomal errors, according to Nussenzweig.
More important, survival rates shot up. Twelve out of 27 mice with the mutant gene developed mammary tumors -- the mouse version of breast cancer -- after about 18 months. But of the mice with the mutant gene who had the 53BP1 protein blocked, only one got mammary tumors after 22 months.
"If you can inhibit 53BP1 early enough, you can restore HR," says Nussenzweig. "When we combine 53BP1 and BRCA1 deficiency, the mice don't get breast cancer."
But there's a catch: even if it works on people, you'll have to introduce it at the right time -- too late, and it might actually do more harm than good.
PARP resistance
For the mutant cells relying on the NHEJ end-gluing pathway, the cells need a protein called poly(ADP-ribose) polymerase, or PARP, to allow the replication repairs to work. Turning off, or inhibiting, PARP, can then kill the cells. That's why now, PARP inhibitors are a promising treatment for breast and ovarian cancers due to BRCA1 mutations. The inhibitors are even the subject of an ongoing phase 2 clinical trial run by AstraZeneca.
Though the results so far are encouraging, Nussenzweig worries that, like all cancers, the BRCA-associated ones can develop resistance to the drug. While many cancer cells would fall victim to the PARP inhibitors at first, others would somehow turn back on the HR process thereby making them, in effect, immune to the drug, as the HR pathway doesn't need PARP to function.
"We propose that one way they get resistant is losing 53BP1," Nussenzweig says. "They would then turn back on the homologous recombination process, just like the mice in the study, allowing them to replicate without PARP. The problem is that they already have the cancer growing, which would then become immune to the PARP inhibitor."
Unanswered questions
Nussenzweig's laboratory is now planning on testing mice with PARP inhibitors, to see if their BRCA-associated cancers acquire resistance to the drugs in this fashion. But he's also eager to explore other unanswered questions about the BRCA1 mutation.
One curious feature of the mutation is that though the BRCA1 gene is found almost everywhere in the body, mutations to it seem to increase risk for cancers only in the breasts and ovaries.
In most cells, if they lose both copies of the BRCA1 gene (as can eventually happen if it's mutated), they don't develop cancer; they die, as cells depend on the HR process for their very survival.