5/21/2013


Scientists have isolated bits of genetic code whose disappearance in breast cancer patients allows the disease to spread to bones and lungs, according to a study to be published Thursday.

When present, the three types of small ribonucleic acid, or microRNA, suppress metastasis, the process by which cancer proliferates and migrates to other organs, the study, published in the British journal Nature, showed.

Metastasis is the overwhelming cause of death in patients with solid tumours. Less than ten percent of women with metastatic breast cancer survive beyond a decade.

Based on experiments with mice and research on cancer patients conducted at the Memorial Sloan-Kettering Cancer Center in New York, the findings could pave the way to drugs that could prevent or treat metastasis not just in breast cancer, but other forms of the disease as well.

More immediately, they will help doctors gauge the possibility that a given patient's cancer will migrate or relapse.

"The gene signature we have identified could offer another tool for assessing the likelihood that cancer will progress," said the study's senior author Joan Massague, a researcher at Sloan-Kettering's Howard Hughes Medical Institute.

Earlier studies reported that certain tumours, including breast cancer, had decreased levels of microRNA. Massague and his colleagues wanted to find out if these tiny molecules that regulate gene activity might play a role in spreading the disease.

The first step -- comparing the genetic profile of non-metastatic and metastatic human breast cancer cells -- showed highly reduced numbers of three kinds of microRNA in the latter, both in the laboratory and in patients.

When the researchers restored the microRNA to normal levels, it greatly reduced the human cancer cells' ability to spread to the lungs or bones of mice.

Further analysis showed that one of these absent microRNA, called miR-126, boosted the proliferation rate of metastatic cells, while the other two -- miR-335 and miR-206 -- helped the cancer cells to infect the lungs or bone.

MicroRNA are tiny strings of nucleotides, the basic building blocks of DNA. They regulate gene activity by repressing or enhancing the work of messenger RNAs (mRNA), another type of molecule that ferries the blueprint for constructing proteins from DNA genes to the cell's ribosomes, the factories where proteins are made.

MicroRNA's play an key role in development, cancer, stress responses and viral infections.

The first set of experiments showed an unmistakable link between the microRNA and metastasis. But what was precise mechanism that caused the cancer to spread?

To find out, the researchers looked to see which genes were regulated by the trio of microRNA they had identified.

Six genes, they discovered, became hyperactive with the loss of miR-335, including two -- SOX4 and TNC -- that were known to control the kind of cell migration that enables cancer to invade other tissues.

When the scientists "knocked down" the activity of these genes, they also reduced the cancer cells' ability to spread.

The final step confirmed the laboratory findings: data from 368 patients with breast cancer showed that tumours in which these miR-335-regulated genes were especially active were much more likely to metastasise.

Scientists are now in a position to develop drugs targeting the genes that contribute to metastasis, said Massague. His findings, as set out in the journal Nature, also hold promise for other types of cancer as well.

"We have basically opened a window into a major future inquiry into such genes," he said.

(AFP)-PARIS, Jan 9, 2008

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