Enhanced DNA-repair mechanism can cause breast cancer

Although defects in the "breast cancer gene," BRCA1, have been known for years to increase the risk for breast cancer, exactly how it can lead to tumor growth has remained a mystery. In the October 15, 2007, issue of the journal Cancer Research, scientists from the University of Chicago and Kyoto University, Japan, suggest that a mechanism that normally repairs damaged DNA may function abnormally in BRCA1 carriers leading to one type of poor-prognosis breast cancer.

Their findings provide insight into how the normal BRCA1 gene suppresses the growth of tumors as well as the nature of the genetic instability that leads to cancer when BRCA1 is defective.

"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 tumors and tumor formation is not normally associated with poor cell growth."

Bishop and colleagues found that the slow growth caused by loss of BRCA1 could be compensated for by increasing the amount of the DNA repair protein RAD51.

RAD51 is involved in homologous recombination, 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 tumors because DNA repair fails. The new work from Bishop and colleagues challenges this view.

"BRCA1-deficiency by itself would probably not cause a tumor," Bishop said, "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 tumors."

Using a public database, Bishop and colleagues examined genomic data from 117 primary breast tumors 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 tumors compared with breast tumors 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," Bishop said, "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 tumor."

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 coworkers 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.

In the future "it will be interesting to determine whether high levels of RAD51 can predict tumor prognosis," said Bishop. "Its also possible that tumor cells with high levels of RAD51 are particularly dependent on that gene for survival and therefore sensitive to drugs that target RAD51"

Source: University of Chicago Medical Center

Related stories:

Previously unseen switch regulates breast cancer response to estrogen
A tiny modification called methylation on estrogen receptors prolongs the life of these growth-driving molecules in breast cancer cells, according to research by scientists at Emory University's Winship Cancer Institute. The results are published in the May 9, 2008 issue of the journal Molecular Cell.
Standard chemo works better against metastatic BRCA1/2 breast cancer than against sporadic tumors
The first study to investigate the effects of chemotherapy on metastatic breast cancer in women with the BRCA1 or BRCA2 gene mutation has shown that standard chemotherapy works better in these patients than in women without the BRCA1/2 mutation.
Looping genes may hold a key to understanding breast cancer
Another piece of the puzzle that is breast cancer has been found by University of Queensland researchers.
Evidence now suggests eating soy foods in puberty protects against breast cancer
Evidence is growing from animal and human studies that genistein, a potent chemical found in soy, protects against development of breast cancer - but only if consumed during puberty, says a Georgetown University Medical Center researcher in the British Journal of Cancer published online today. The challenge now, she says, is for scientists to understand precisely why soy appears to provide a shield against the most common cancer in women.
Research links stress and breast cancer
Research findings from a Queen’s University study have for the first time uncovered a possible biological link between severe psychological stress and an increased risk of developing breast cancer.
Study reveals why certain ovarian cancers develop resistance to platinum-based chemotherapy
A team of researchers led by Fred Hutchinson Cancer Research Center has identified a new mechanism that explains why some recurrent ovarian tumors become resistant to treatment with commonly used platinum-based chemotherapy drugs such as cisplatin and carboplatin. They describe their research online Feb. 10 in the journal Nature.
BRCA1 mutation linked to breast cancer stem cells
A new study may explain why women with a mutation in the BRCA1 gene face up to an 85 percent lifetime risk of breast cancer. Researchers from the University of Michigan Comprehensive Cancer Center found that BRCA1 plays a role in regulating breast stem cells, the small number of cells that might develop into cancers.
New pathway provides more clues about BRCA1 role in breast cancer
A breast cancer gene's newly discovered role in repairing damaged DNA may help explain why women who inherit a mutated copy of the gene are at increased risk for developing both breast and ovarian cancer.

News discussion:

Medicine & Health news