A mechanism that is known to repair damaged DNA, functions abnormally in carriers of 'breast cancer gene' BRCA1, causing one type of poor-prognosis breast cancer, a new study has found.
Though defects in the gene are known to increase risk of breast cancer, how this causes tumour growth has remained a mystery.
Advertisement"If you take a normal, healthy cell and get rid of BRCA1, you end up with an unhealthy, slow-growing cell," said Douglas Bishop, PhD, associate professor of radiation and cellular oncology at Chicago and principal investigator of the study.
"That's a bit of a paradox, because loss of BRCA1 also causes tumours and tumour formation is not normally associated with poor cell growth,' he added.
The study has found that increasing the amount of the DNA repair protein RAD51 could compensate for the slow growth caused by loss of BRCA1.
RAD51 is involved in homologous re-combination, a method used by cells to repair damaged DNA. In homologous recombination, organisms heal broken chromosomes using an unbroken chromosome copy as a template.
BRCA1 itself promotes DNA repair through recombination and the conventional view is that loss of BRCA1 causes tumours because DNA repair fails. The new work from Bishop and colleagues challenges this view.
"BRCA1-deficiency by itself would probably not cause a tumour, but cells that manage to compensate for the BRCA1 defect in repair by ramping up RAD51 levels are likely to be less genetically stable than normal cells and therefore more prone to form tumours," Bishop said.
Bishop and colleagues examined genomic data from 117 primary breast tumours for evidence of elevated levels of RNAs for genes involved in homologous recombination. They found that the level of RNA for three genes -- RAD51 and two of its key accessory factors -- was significantly higher in BRCA1-deficient tumours compared with breast tumours that were not associated with BRCA1 mutations.
"High levels of RAD51 may help cells that lack BRCA1 overcome the defects in recombination caused by loss of BRCA1. But the recombination that occurs in this situation may be abnormal and may actually cause mutations which in turn lead to the development of a tumour," Bishop said,
When the researchers took normal, healthy cells in culture and disabled the BRCA1 gene, the cells survived, but grew slowly and were unable to repair DNA damage normally. When Bishop and his co-workers increased the amount of RAD51 in these cells, however, the ability of cells to repair DNA damage was restored and the mutated cells grew more quickly.
"It will be interesting to determine whether high levels of RAD51 can predict tumour prognosis," said Bishop.
"Its also possible that tumour cells with high levels of RAD51 are particularly dependent on that gene for survival and therefore sensitive to drugs that target RAD51,' he added.
The study is published in the October 15, 2007, issue of the journal Cancer Research.
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