Stanford scientists find new marker to identify severe breast cancer cases

Women with breast cancer whose tumors express high levels of a particular genetic marker are significantly more likely to die from their disease than are those with more normal levels, according to researchers at Stanford University School of Medicine. The finding implies that blocking the action of the marker — a newly recognized type of RNA — could one day be an effective way to prevent metastasis and improve survival for these women, who make up about one-third of all breast cancer patients.

"We've found that this RNA, called HOTAIR, is a really important player in human health," said Howard Chang, MD, PhD, an associate professor of dermatology and a member of the Stanford Cancer Center. "When it becomes dysregulated in breast cancer, it drives the tumor cells to metastasize and worsens a woman's prognosis."

It does this, the researchers believe, by tinkering with the cells' genome, laying bare regions that are normally kept bundled up and silent in adult cells and silencing others that are normally expressed. "As a result, the cells' gene expression profiles begin to look much more like those of embryonic fibroblasts, and they acquire attributes that allow them to thrive in other parts of the body," said Chang.

Chang is the senior author of the work, which will be published on April 15 in the journal Nature. He was named a Howard Hughes Medical Institute Early Career Scientist in March 2009. He collaborated with researchers at Johns Hopkins University School of Medicine, Academic Medical Center in the Netherlands, the Broad Institute of Harvard, the Massachusetts Institute of Technology and Applied Biosystems Inc. to conduct the research.

Until recently, RNA was thought to exist mostly to carry protein-building instructions from the DNA in the nucleus to protein-making factories called ribosomes in the cell's cytoplasm. However, it's become more clear in the past few years that RNA is much more versatile. Some types can affect how genes are expressed by binding to and even modifying the structure of DNA.

Chang and his colleagues have been studying HOTAIR — named for "HOX antisense intergenic RNA" — for several years now, trying to understand why RNA molecules that aren't translated into proteins are so prevalent and what other things they might be doing. "There's something like 10,000 of these large intervening non-coding RNAs, or lincRNAs, in the human genome," said Chang. "They represent a new class of genes that don't make protein, but that affect gene expression in some mysterious way."

In 2007, Chang and his colleagues reported that HOTAIR plays an important role in helping cells know their location in the body and what they are supposed to become. It works by activating a group of enzymes called the Polycomb Repressive Complex 2, or PRC2, involved in DNA packaging. The finding was the first to show that lincRNAs can affect the expression of distant genes on other chromosomes and gave an inkling of their global importance in the body.