Novel RNA marker identifies severe breast cancer cases
MedWire News: Women with breast cancer whose tumors express high levels of a newly recognized type of RNA are significantly more likely to die from their disease than are those with normal levels, according to US researchers.
"We've found that this RNA, called HOTAIR, is a really important player in human health," said Howard Chang, from the Stanford Cancer Center in California. "When it becomes dysregulated in breast cancer, it drives the tumor cells to metastasize and worsens a woman's prognosis."
HOTAIR, named for “HOX antisense intergenic RNA", is a large intervening non-coding RNA (lincRNA) that works by activating a group of enzymes called the polycomb repressive complex (PRC)2, which is involved in DNA packaging.
In the current study, Chang and colleagues compared levels of HOTAIR expression in normal human breast tissue with that of primary breast cancer tumors and tumors that had metastasized to other parts of the body.
They found that nearly one third of primary tumors expressed levels of HOTAIR that were over 100 times higher than those found in normal breast tissue. Metastatic tumors expressed levels of HOTAIR that were hundreds or thousands of times higher.
The researchers repeated the analysis using an independent panel of frozen breast cancer samples from 132 women with extensive follow-up. They found that those women whose primary tumors expressed high levels of HOTAIR were approximately three times more likely than their peers with normal breast epithelia to develop tumor metastasis and to die in the subsequent 15 years.
To understand how HOTAIR affects tumors cells, Chang and team studied several breast cancer cell lines. They found that enforced expression of HOTAIR in epithelial cancer cells induced genome-wide retargeting of PRC2 to an occupancy pattern resembling that of embryonic fibroblasts. This led to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2.
Conversely, loss of HOTAIR inhibited cancer invasiveness, particularly in cells that possess excessive PRC2 activity.
“These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy,” conclude Chang and co-authors in the journal Nature.
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By Laura Dean