Doctors have long known that women with a mutated version of the BRCA1 gene face a significantly higher risk of developing breast cancer because their bodies can’t properly repair damaged DNA.
However, the biological mechanisms behind that problem have been unknown.
New research led by scientists from The Salk Institute in La Jolla appears to have cracked some of that mystery and, along the way, uncovered a potential method for detecting breast cancer much earlier than mammograms are capable of doing.
“This allows us to design search strategies for future therapies, both to prevent inherited breast cancer and also to treat the cancers that have already developed,” said Salk biologist Gerald Pao.
The damaged BRCA1 gene is responsible for about 5 percent of the 230,000 new cases of breast cancer diagnosed each year in the United States, according to the National Cancer Institute.
The results of the work by Pao and seven collaborators from Salk, the Netherlands Cancer Institute, Beth Israel Medical Center in New York and the Cleveland Clinic, were published Thursday in the prestigious scientific journal Nature.
Using laboratory mice that were genetically engineered to lack the BRCA1 gene, the scientists found that a certain portion of DNA in the animals’ breast and brain cells weren’t packaged as tightly as it was when the gene was present.
The researchers made the same observations in breast tumor cells taken from humans.
The genetic material is part of a large portion of the genetic code known as “junk” DNA that traditionally was believed to play little or no role in cellular function.
However, more recent research has revealed that some junk DNA actually does contribute to certain cell operations.
In this case, when the junk DNA observed by Pao and his colleagues was loosely packaged it produced RNA (messenger genetic coding) that caused breaks in other parts of the DNA and interfered with normal cell division.
“If you don’t package your DNA correctly, that can lead to all sorts of problems,” Pao said.
The rogue genetic coding is also known as satellite DNA because of its remote position in relation to the main cluster of genetic material.
The initial discovery came seven years ago when Pao and Quan Zhu, a fellow cancer biologist at Salk, accidentally stumbled across the packaging problem.
“One night, Quan and I were looking under the microscope,” Pao said. “Just by chance, we saw that the DNA wasn’t packaged correctly.”
A blood test capable of detecting the RNA produced by the loosened junk DNA could provide an earlier way of diagnosing breast cancer, particularly in younger women whose healthy firmer breast tissue often hides tumors in mammograms, Pao said.
Before that happens, researchers must conclusively tie the disease to the genetic problems triggered by the loose bundling of the junk DNA.
While the work by Pao and his colleagues stopped short of that achievement, the effort still “might herald a breakthrough,” wrote Cambridge Cancer Centre researcher Ashok Venkitaraman in a review of the research that accompanied the Nature publication.
“Regardless of the remaining ambiguities, in describing an association between satellite DNA transcription, BRCA1 loss and genomic instability, (the) work reveals an intriguing new pathway for tumor suppression,” said Venkitaraman, who was not involved in the research.